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COPYRIGHT DEPOSE 



TEXTBOOK 



OF 



PHABMACOLOG-Y 



THEEAPEUTICS 



ACTION OF DRUGS IN HEALTH AND DISEASE 



BY 

ARTHUR R. CUSHNY, M.A., M.D., Aberd. 

Professor of Materia Medica and Therapeutics in the University of Michigan; iobi 
Thompson Fellow in the University of Aberdeen and Assistant in the 
Pharmacological Institute of the University of Strassburg. 



THIRD EDITION, REVISED AND ENLARGED 



ILLUSTRATED WITH FIFTY-TWO ENGRAVINGS 




LEA BROTHERS & CO. 
PHILADELPHIA AND NEW 5TORK 



THE LIBRARY OF 

CONGRESS, 

Two Copies Received 

JAN 16 1903 

ft Copyright Entry 

CLASS *" XXc, No. 

COPY B. 



1^ 



CH 



if 



Entered according to the Act of Congress in the year 1903, by 

LEA BROTHERS & CO. 
In the office of the Librarian of Congress. All rights reserved. 



OSWALD SCHMIEDEBERG, 



DEM MEI8TEB, YOM SOHtJLER GEWIDMET. 



PREFACE TO THE THIRD EDITION. 



During the eighteen months which have elapsed since the appear- 
ance of the second edition, several important advances have been made 
in pharmacology, necessitating corresponding changes in the text. The 
most interesting of these advances is the authoritative and, it is to be 
hoped, final determination of the food value of alcohol, which has been 
treated in more detail than in former editions. The increasing use of 
cocaine as a local anaesthetic, and the introduction of the subarachnoid 
method of medication required an expansion of the chapter on this 
drug, and the same may be said of the pages devoted to the adrenal 
gland. Numerous minor changes have been made to bring the text up 
to date and several new illustrations have been added. 

Some experience in teaching pharmacology has led me to devote the 
last part of the term to a review, in which the drugs are classified ac- 
cording to their therapeutic uses. There is then an opportunity to 
compare the relative advantages of, and the special indication- for 
different remedies, which is necessarily absent in the earlier part of the 
course. In order to facilitate this part of the work, such a classifica- 
tion has been appended to this edition. 

I have again to express my gratitude to the teachers of pharmacol- 
ogy for the welcome accorded the first two editions, as well as for 
many helpful suggestions for this one. 

A. R. C. 

(5) 



PREFACE TO THE FIRST EDITION. 



The following pages were written to supply a want which I have 
felt keenly in teaching the subject of pharmacology +o students who 
have completed the purely scientific branches of medicine and arc be- 
ginning their clinical studies. My object has been to bridge over the 
hiatus which exists between the phenomena occurring in the normal 
organism and those which are elicited in the therapeutic use of drugs, 
to show how far the clinical effects of remedies may be explained by 
their action on the normal body, and how these may in turn be cor- 
related with physiological phenomena. It necessarily follows that the 
subject is treated from the experimental standpoint, and that the re- 
sults of the laboratory investigator are made the basis of almost every 
statement. Where these fail to elucidate the therapeutic effe- 
even to suggest a possible explanation, I have preferred to leave the 
question undiscussed rather than to call on such occult del ex machina 
as alterative or tonic actions. 

Two great difficulties present themselves at the outset to the writer 
on pharmacology who is not satisfied to take his statements at second 
hand, or to formulate explanations from his unaided inner conscious- 
ness ; these are the overwhelming literature on the subject, and the 
wide limits of the field of study. As regards the first, I have read, as 
far as was in my power, the original papers of importance, and in ord< r 
to facilitate the work of others who may wish to follow this, the only 
satisfactory method of study, have appended a bibliography to each 
chapter. It was impossible within the limits of a textbook to make 
this complete, or even to enumerate more than a few of the works con- 
sulted, and I have accordingly selected those which appeared most 
important, and those which were furnished with the most complete 
bibliography. 

As regards the scope of the work, I have attempted to give the 
present standpoint of knowledge of such bodies as are of therapeutic or 
toxicological interest, and also of those which, possessing in themselves 
no immediate interest in practical medicine, have thrown important 
light on biological problems, and are accordingly likely to be n 
to in scientific literature. 



8 PREFACE. 

Unfortunately, a writer on this subject cannot as yet restrict his at- 
tention to these classes, but must refer at more or less length to many 
drugs which possess little interest either from a therapeutic or a scien- 
tific point of view. It is true that jthe more advanced teachers of 
medicine have very properly abbreviated their lists of remedies, until 
lose generally employed may be enumerated in units where they were 
once counted in scores, but the student on going into practice meets 
numbers of drugs previously unknown to him, and not appreciating 
that these have already been tried and discarded by his teachers, is 
tempted to fall into the slough of unreasoning empiricism. There is 
Irtill a tendency even among the educated to ascribe therapeutic virtues 

every new weed and every new product of chemical industry/ and 
the teacher of pharmacology must not only point out the good, but has 
the more ungrateful task of condemning the worthless. The period of 
constructive pharmacology has scarcely dawned ; at present its chief 
function is destructive and critical. 

In dealing with each drug, I have attempted to unify the whole ac- 
tion by using the most distinctive feature as a centre around which to 
group the less important symptoms. Where, as is often the case, 
there is a divergence of views among authorities, I have generally pre- 
sented only one side of the question, except in very important subjects. 
This dogmatic method has of course its drawbacks, but is, I think, 
preferable to involving the student in a labyrinth of arguments and 
counter-arguments, the respective weight of which he is quite unable 
to estimate. 

The preparations enumerated are those included in the United States 
and the British Pharmacopoeias, and such others as seemed of sufficient 
importance. I have attempted to indicate by special type (small capi- 
tals) those that are more generally used. 

Some explanation may seem necessary for the introduction of the 
word " therapeutics " in the title, in view of the fact that pharmacology 
is stated in the introduction to embrace all that part of therapeutics 
which can be treated of apart from clinical lectures. This definition 
is not universally used, however, and it has been felt advisable to in- 
dicate more distinctly the scope of the work by adding the more 
familiar term. 

To those acquainted with the Grundriss der Arzneimittettehre of 
Schmiedeberg, it is unnecessary to state that this volume has been 
largely inspired by that classical work. Some chapters may in fact 
be regarded as merely expansions of those issued from the Strassburg 
laboratory, but this must necessarily be the case in any work which 



' PREFACE. 9 

pretends to treat the subject from the experimental standpoint. The 
use of such a model naturally exposes the writer to the criticism that 
he has fallen short of the original standard, especially when such 
divergences are made from it as occur in this work. Bui if I have 
departed from the letter in some respects, I hope that at least the spirit 
of the Grundriss has been preserved in these pages. I must acknowl- 
edge my indebtedness for references to papers which might have 
otherwise escaped my notice to the following textbooks: Robert's 
Lehrbuch der Intoxicationcn, Lewin's Nebenwirhmgm der Arzneimittel, 
Husemann's Pflanzenstoffe, Harnack's ArzneimitteUehre, H. C. Wood's 
Therapeutics, its Principles and Practices and Stokvis* Lc<;<>nx de Phar- 
macotherapie. 

Finally, I have much pleasure in acknowledging the assistance of my 
colleagues in the preparation of this work, particularly that of Profes- 
sor Huber, who furnished several of the illustrations. Dr. (J. \\. 
Wallace has put me under lasting obligations through the patience and 
care which he has bestowed on the tedious task of proof-correct imi. 
and I must thank Dr. W. Mogk also for his assistance in this part of 
the work. 

University of Michigan, 
Ann Arror, Mich., June, 1899. 



CONTENTS. 



Pass 

Introduction 17 

Mode of action of drugs, stimulation, depression, irritation . 20 

Elective affinity of drugs, protoplasm poisons .... 22 

Remote, local and general action ....... 23 

Chemical composition and pharmacological action . . . 24 

Conditions modifying the effects of drugs 25 

Methods of administration .80 

Chemical characters of drugs . . . . . . . :.l 

Pharmacopoeias and pharmacopceial preparations . . . .87 

Classification of drugs , 41 



PART I. 

ORGANIC SUBSTANCES WHICH ARE CHARACTERIZED 

CHIEFLY BY THEIR LOCAL ACTION . . . .45 

1. Demulcents ........... 45 

2. Emollients 49 

3. Sugars and flavoring substances . . . . . . .54 

4. Simple bitters. 56 

5. Volatile oil series Gl 

Flavoring agents and carminatives 66 

Pepper group 72 

Malodorous volatile oils .71 

Genito-urinary disinfectants 75 

Uva ursi . .77 

6. Skin irritants and counter-irritation 7^ 

Turpentine oil group 86 

Mustard 

Cantharidin series 

7. Vegetable purgatives 

Purgative oils. 

Anthracene purgatives 

Jalapin and colocynthin group ...•••• 

8. Vegetable astringents — tannic acid group 

9. Anthelmintics 

Male fern 



Cusso I 20 

Granatum 

Santonin . . . . 



12 CONTENTS. 

PART II. 

Page. 
ORGANIC SUBSTANCES CHARACTERIZED CHIEFLY BY 

THEIR ACTION AFTER ABSORPTION 127 

1. Narcotics of the methane series. Alcohol -chloroform group . .127 

Alcohol 131 

General anaesthetics — ether and chloroform ..... 154 

Nitrous oxide. .......... 183 

Soporifics — chloral ......... 187 

2. Strychnine — Nux vomica ........ 196 

3. Opium series 207 

Minor drugs of the opium series ....... 228 

4. Hydrastine and hydrastinine ........ 230 

5. Cannabis indica .......... 233 

6. Apomorphine. .......... 235 

7. Prussic acid 239 

8. Caffeine 245 

Coffee and tea .......... 254 

9. Curara 256 

10. Coniine, gelseminine and sparteine ...... 261 

Coniine 261 

Gelseminine ........... 265 

Sparteine . .266 

11. Nicotine 268 

Tobacco 276 

12. Lobeline 278 

13. Atropine series .......... 279 

Agaricin. ........... 301 

14. Cocaine 302 

15. Pilocarpine and muscarine ........ 315 

16. Physostigmine .......... 324 

Resume 330 

17. Aconitine 332 

18. Veratrine 338 

19. Emetine (ipecacuanha) 343 

20. Colchicine 347 

21. Saponin, sapotoxin and solanine 350 

22. Aspidosperma or quebracho ........ 356 

23. Quinine 357 

24. Antipyretics (acetanilide and antipyrine series) .... 373 
25! Antiseptics of the aromatic series (carbolic and salicylic acid series) 390 

Carbolic acid 398 

Cresol 404 

Thymol 405 

Eucalyptol 406 

Resorcin. 406 

Pyrogallol 407 

Naphtalin and naphtol 408 



CONTENTS. L3 

Paob. 

Tar 4io 

Creosote 411 

Ichthyol ... 412 

Salicylic acid 413 

Other aromatic oxy acids . 422 

Sulphocarbolates 422 

Benzoic acid 

Nitrobenzol compounds. 435 

Naphthylamine . . 426 

Toluylendiamine . . . . 427 

Benzol . . . 4l'7 

Pyoctanine . . . . 428 

26. Formaldehyde 428 

27. Camphor 430 

28. Picrotoxin 436 

29. Digitalis series . . . 44o 

30. Suprarenal or adrenal glands 463 

31. Nitrites 468 

32. Ergot 476 

PART III. 

COMBINATIONS OF THE ALKALIES, ALKALINE EARTHS, 

- ACIDS AND ALLIED BODIES 485 

Salt-action . . . . . . . . . . .485 

1. Sodium chloride and water 490 

2. Potassium salts . . . .498 

Lithium, caesium, rubidium ........ 499 

3. Ammonium 500 

4. Bromides 504 

5. Iodides 510 

6. Iodine . . . . .517 

7. Iodoform . . . . 521 

8. Fluorides . 525 

9. Chlorates 526 

10. Nitrates 531 

11. Sulphites 

12. Hypophosphites 

13. Saline cathartics ......... 

14. Hydrates and carbonates of the alkalies .... 
Piperazine and Urotropine ....... 

15. Acetate series. 

16. Ammonia and carbonate of ammonia 

17. Oxalates 

18. Acids 

19. Calcium 

20. Barium and strontium . 

21. Sulphides and sulphur 



14 CONTENTS. 

Page. 

22. Charcoal 581 

23. Boracic acid and borax 582 

24. Carbonic acid 584 

25. Chlorine and bromine 586 

26. Oxygen 588 

27. Peroxide of hydrogen ......... 591 

28. Phosphorus 594 

29. Arsenic 607 



PART IV. 

THE HEAVY METALS 625 

1. Antimony 633 

2. Mercury 638 

3. Iron 659 

4. Lead 674 

5. Copper 684 

6. Zinc 688 

7. Silver 691 

8. Bismuth 696 

Cerium . . . . 700 

9. Aluminium and alum 700 

10. Minor metals . .703 

Gold 703 

Platinum . . . . . . . . . . .703 

Chromium ........... 704 

Manganese 705 



PART V. 

FERMENTS, SECRETIONS AND TOXALBUMINS . . .709 

1. Digestive ferments 709 

Pepsin 709 

Pancreatic ferments 710 

Vegetable ferments 711 

Diastase. 711 

2. Bile 712 

3. Internal secretions . 714 

Thyroid gland 715 

Other internal secretions 722 

4. Toxalbumins 724 

5. Cod-liver oil 726 

6. Phloridzin 729 



PART VI. 
MENSTRUA AND MECHANICAL REMEDIES .... 731 



A TEXT BOOK OF PHARMACOLOGY. 



INTRODUCTION. 

Pharmacology is the study of the changes induced in living organ- 
Isms by the administration in a state of minute division of such un- 
organized substances as do not act merely as foods. Many of the best 
known of these substances are used to counteract the effects of die 
or to reinforce the tissues in their struggle to maintain their function-, 
when these are rendered abnormal. These substances are known as 
drugs, and the art of applying drugs in disease, is Therapeutics. Other 
substances are of little or no value in disease, but are of importance 
because they act as poisons, that is, cause dangerous or fatal symptoms 
in manor animals, when they are ingested in quantity. The practical 
study of the effects of these poisons in man — the diagnosis and the 
treatment of poisoning, and the methods of detecting the poison — is 
termed Toxicology. But the explanation of the symptoms induced by 
chemical substances, and their study, as apart from their practical ap- 
plications, belong to the field of pharmacology, which includes not only 
the effects of drugs and poisons, but those of any substance which 
induces changes in the living organism, whether those changes are of 
benefit to it, injurious, or quite indifferent. 1 

The substances must, of course, conform to the requirements of the defini- 
tion. Thus, a needle introduced into the tissues induces effects which are 
outside the field of pharmacological investigation, because it is not in a state 
of minute division. But the iron of the needle may be reduced to a line 
powder and induce changes in the body which are then the legitimate subject 
of research. Similarly the drug must be introduced from without, for many 
active agents are formed within the body, but their study belongs rather t<> 
the departments of physiology and pathology; and the effects of organized 
bodies introduced from without are now studied under bacteriology. Phar- 
macology is really a department of biology, very closely related to the other 
sciences included by that term. Thus, as physiology is the study of the life 
of the normal organism, pharmacology is the study of the organism rendered 
abnormal by drugs, while in pathology the phenomena of life under disease 
are examined. All three subjects may be pursued without reference to tin- 
practical needs of medicine, and all three are closely interconnected and 
mutually dependent, for, in many instances, the normal condition id' an 
organ can be recognized only by considering; the results of its destruction 
by disease (pathology), or of its paralysis or stimulation by chemical agents 

1 It is quite impossible to distinguish between drugs and poisons. Almost all reme- 
dies given in excess cause dangerous or fatal symptoms, while many poisons are valuable 
remedies in small doses. Some bodies may in fact he remedies, food*, or poison- 
ing to the quantity ingested and the method of application. 
2 17 



18 INTRODUCTION. 

(pharmacology). Similarly, many of the features of disease are now rec- 
ognized to be due to the presence of unorganized poisons formed in and by 
the tissues, and it accordingly becomes difficult to accurately define the 
limits of pathology and pharmacology. Thus, the toxines formed by microbes 
resemble in their action some of the ordinary drugs or poisons, and might be 
considered along with these. But the study of these toxines is so closely 
bound up with that of the microbes from which they originate, that it has 
been thought better to leave them to be treated by special text books on bac- 
teriology. For a similar reason the antitoxines, which play so prominent a 
role in modern therapeutics, may be excluded from treatises on pharmacol- 
ogy, for the present at any rate. 

Even when these limitations are accepted, pharmacology has an 
enormous field to cover, and one which has been only very partially ex- 
plored at the present day, in spite of the unremitting industry of many 
investigators. But a small part of the subject has been sufficiently 
developed to admit of text-book treatment, that namely, which is con- 
cerned with drugs used in therapeutics and with the commoner poisons. 
The slow advance of pharmacology is partly due to its position midway 
between the biological sciences and practical therapeutics, for while the 
biologist confounds it with clinical study, the clinician regards it as an 
experimental science. Its relation to biology has already been men- 
tioned and its relation to practical therapeutics is no less close, for the 
effects of drugs in disease are as much a part of pharmacology as is their 
action in the normal organism. The aims of the pharmacologist and the 
clinician are not identical, however. The former seeks to solve the 
problem how the drug acts in a given case, while the primary object of 
the latter is to remedy the condition by any means in his power. Thus, 
in a case of heart weakness, the clinician prescribes some remedy which 
he has found of benefit in other similar cases, and regards only as of 
secondary interest the question which to the pharmacologist is the 
absorbing one, namely, whether the drug acts on the heart directly or 
through some other organ. Of course the results are of mutual ad- 
vantage, for the physician supplies the experimental investigator with 
new facts and with new fields of inquiry, while the latter may indicate 
more exactly the conditions in which the drug is likely to be of benefit 
in the future by defining the method in which it acts. It is, therefore, 
much to be regretted that differences of opinion so often arise between 
these two classes of observers, for these can only retard the progress of 
both the science and the practical art. Doubtless there are often faults 
on both sides. The scientist sometimes insists too strongly on induc- 
tions drawn from a limited number of animal experiments, and refuses 
to admit results which have been obtained in thousands of cases of dis- 
ease by competent observers. On the other hand, the therapeutist often 
lays too little weight on the general principles governing the interaction 
of the drug and the organism. Both often exceed the limits of their 
provinces, the scientist in refusing to admit effects of which he has per- 
force but a small experience, the clinician in attempting to refute de- 
ductions founded on experiments which he has no opportunity of per- 
forming. An example may render the relation of these allied subjects 



PHARMACOLOGY. 1<J 

clearer, and one has been recently offered in the discussion regarding 
the effects of iron. This metal has been used for many years in a form 
of anaemia, and its curative properties are attested by many thousands 
of cases and by whole generations of practical physicians. A phar- 
macologist, therefore, exceeds his province when he expresses doubt 
regarding this clinical fact simply because he is unable to explain it, 
but he is within his rights in discussing the means by which iron acts 
as a remedy. The clinician, on the other hand, enters on a pharma- 
cological question when he attempts to determine whether iron acts by 
absorption or by its presence in the bowel, and must base his argu- 
ments on scientific experiment and not on his clinical experience of the 
curative effects of the metal. Fortunately for the progress of medicine 
and pharmacology, the scientific clinician is imbued with the desire to 
ascertain the methods in which drugs act as well as to cure disease, and 
thus unites clinical observation with pharmacological research. It is 
to be anticipated that the results of the practical physician and of the 
experimental investigator will come into more complete accord as 
more exact methods of clinical research are used by the former, and 
a wider laboratory experience is attained by the latter. But both 
methods are necessary to the complete knowledge of the action of a 
drug. Animal experiment cannot be dispensed with, for only thus 
can the action of drugs be ascertained in detail and expeditiously, and 
at the present time, when a new remedy appears almost every week, it 
is impossible to await the verdict of the clinics to separate the useful 
from the worthless, even if it were permissible to apply to the human 
subject drugs of unknown action and potency. 

Pharmacology is one of the most recent developments of medical and 
biological science. It is true that from the earliest times attempts have 
been made to explain the effects of drugs on the then prevailing theo- 
ries of pathology, but the objective study of the action of drugs on the 
organism has been a development of the nineteenth century, or it might 
almost be said, of the second half of it. During this period the same 
methods of research have been adopted as had earlier proved so fruitful 
in physiology and pathology, and with equally happy results. The 
study of drugs was termed Materia Mediea up to this time, and com- 
prised an examination of their botanical and chemical properties along 
with some account of the diseases in which they had proved of value. 
This descriptive rather than experimental study has been continued 
under the name of Pharmacognosy, but is now pursued by pharmacists 
chiefly. Undoubtedly the student of medicine ought to know those 
characters ol drugs which are of importance as modifying their action 
and application, but it is undesirable that his valuable time should be 
occupied in the detailed description of crude substances, which he may 
probably never have an opportunity of seeing in his future practice. 

Another subject which now occupies a much less prominent position 
in medical study than formerly, is Pharmacy, or the art of preparing 
drugs for therapeutic use. Some general knowledge of the methods 
used is no doubt indispensable to the educated physician, but the dc- 



20 INTE OD UCTION. 

tails may be left to the pharmacist. Pharmacy will probably occupy a 
still more subordinate position in medical education as the tendency 
to include only one or two drugs in a prescription becomes more wide- 
spread. As long as a dozen or more components went to make one 
mixture, it was of importance to know their solubility and their inter- 
actions, but with the decay of the complex prescription the study of 
pharmacy by medical students has certainly become less imperative. 

MODE OF ACTION OF DRUGS. STIMULATION, 
DEPRESSION AND IRRITATION. 

A small number of drugs affect the organism only through their phy- 
sical properties, as when an inert oily body is applied to X n abraded 
surface and promotes its healing by protecting it from irritation and 
from the evaporation of fluid, or when common salt absorbed into the 
blood changes its osmotic tension, and thus alters the ^distribution of 
fluids in the tissues. 

But the great majority of drugs act through their chemical affinity 
for certain forms of living matter. They probably form temporary 
combinations with some forms of protoplasm, and alter the function of 
all cells which contain these forms. At least this is the only explana- 
tion of their affecting certain organs while others escape their influ- 
ence. To take an example, the cells of the spinal cord normally receive 
sensory impressions from the exterior and send out motor impulses. 
But under strychnine the motor impulses are much more violent than 
usual, and this may be expressed by saying that the combination of 
strychnine and cord protoplasm functions more powerfully than unal- 
tered cord protoplasm. The activity is changed, however, only in de- 
gree and not in kind ; the reflex movement may be more powerful or 
less powerful than normally, but it remains a reflex movement and can- 
not under any circumstances partake of the nature of a voluntary move- 
ment. In other words, the action of drugs is quantitative and not 
qualitative, the activity of living matter may be changed, but the form 
which the activity assumes is unchangeable. 

In recent years much attention has been paid to a series of natural 
phenomena occurring in the border-land between physics and chem- 
istry and the application of the results of " physical chemistry " to 
pharmacology has proved of great value already and promises to eluci- 
date in the future many problems which have hitherto been unap- 
proachable. Examples of such applications will be met in the Meyer- 
Overton theory of narcosis and in the chapters on salt action. The 
tendency of study in this direction is to reduce the class of reactions 
which have hitherto been ascribed to special chemical affinity between 
drugs and protoplasm and to attribute many of the changes induced by 
drugs to the physical structure of the living cell rather than to its 
chemical constitution. 

Drugs which increase the activity of any organ or function are said 
to stimulate it, while those which lessen the activity are said to depress 



MODE OF ACTION OF DRUGS. 21 

it. Another condition induced by drugs is irritation, for although this 
term is often applied loosely as a synonym for stimulation, the two 
conditions are not identical. Stimulation is properly used to indicate 
an increase in the specialized function of a cell, producing, for instance, 
in the spinal cord an increase in the reflex excitability. Irritation, 
on the other hand, is used rather in reference to the changes in the 
conditions common to all forms of living matter, that is, it indicates a 
change in the nutrition and growth of the cell, rather than in the 
specialized functions. Irritation may thus be induced in all kinds 
of tissues and is the commonest change caused by drugs in the less 
differentiated forms such as the connective tissues and ordinary 
epithelia ; while stimulation is met with in the more highly specialized 
cells, such as those of the heart, nervous system, or secretory glands. 
In many instances the irritant action of drugs may be explained by 
their known reactions with the proteids of the cell ; for example, sub- 
stances which dissolve preteids, or precipitate them, or withdraw fluid 
from them, all tend to cause irritation when they are applied to living 
tissues. In other cases irritation appears to be induced through some 
chemical action the nature of which is quite unknown. 

When stimulation is prolonged or excessive, the protoplasm gener- 
ally becomes depressed and finally loses its activity entirely (paralysis). 
Some authorities have asserted that depression is invariably preceded 
by stimulation, and that stimulation sufficiently prolonged invariably 
leads to depression and paralysis. Both statements are too absolute, 
although they are true in the great majority of cases. For example, 
the action of atropine on the terminations of the cardiac inhibitory 
nerves is purely depressant. Even the most minute quantities of this 
alkaloid never increase the activity of these terminations, for if a quan- 
tity too small to paralyze them is ingested, it has apparently no effects 
whatever, and as the dose is increased, the first effect is paralysis. 

Depression, whether induced directly, or following on stimulation, 
has been shown in several instances to resemble the fatigue induced by 
the prolonged exercise of the normal organ, and it is probably true that 
depression and fatigue are, in all instances, identical in appearance, al- 
though not necessarily identical in cause. For example, the phenom- 
ena of fatigue of the terminations of the motor nerves in muscle re- 
semble exactly those induced by curara, but in the former the cause 
may be that the conducting substance of the nerve ends has been used 
up by the repeated passage of impulses, while in the latter the conduct- 
ing substance is so changed that it becomes incapable of transmitting 
stimuli to the muscles. The final result is, of course, the same ; there 
being no available conducting substance, impulses fail to reach the 
muscle. But the fatigued terminations rapidly recover, as conducting 
substance is reformed, while the curarized recover only when the poison 
is eliminated. 

In most cases an excessive dose of a stimulating poison leads to de- 
pression and paralysis. The cell becomes functionally dead, bul it' the 
failure of its function does not involve the death of the oix r :uii<m, it 



22 INTRODUCTION. 

may recover and reassume its ordinary function as if no stage of inac- 
tivity had intervened. Excessive irritation, on the other hand, leads 
to actual death and disintegration, from which there is no recovery. 
For example, the cells of the spinal cord are first stimulated, and later 
paralyzed by a large dose of strychnine, but this is not fatal to cold- 
blooded animals, and after a few days the spinal cord regains its nor- 
mal function, as the poison is eliminated. On the other hand, the in- 
jection of an irritant into the subcutaneous tissues causes dilatation of 
the vessels, effusion of fluid, and increased growth and rapid division 
of the cells. If only a small quantity be injected, this condition is 
recovered from, although it generally leaves evidence of its presence in 
the form of an increase in the fibrous tissue. But if the irritation be 
intense, the cells undergo degeneration and die, and an abscess is 
formed. The cells thus destroyed can never recover as the paralyzed 
ones do. They are either absorbed, or removed by the opening of the 
abscess, and their room is filled by the overgrowth of the neighboring 
tissues. 



ELECTIVE AFFINITY OF DRUGS. PROTOPLASM POISONS. 

Most drugs have an elective affinity for certain definite tissues. 
Thus, some attack the heart only, others the central nervous system 
and others the terminations of the motor nerves in muscle. Among 
the cardiac poisons again, some act on the ventricle, others on the 
auricle, and among the poisons of the central nervous system, some act 
primarily on the cortex, others on the medulla oblongata and others 
on the spinal cord. This elective affinity is not merely a question of 
degree, as is sometimes stated, for a drug which has a powerful action 
on the brain, may have no effect on the heart except when administered 
in such quantities as alter the physical characters of the blood. A 
drug may even alter different structures in diametrically opposite direc- 
tions. Thus, atropine depresses certain nerve terminations, but stimu- 
lates the brain, and curara, which paralyzes the peripheral terminations 
of the motor nerves, stimulates the spinal cord. In some instances 
the immunity of a cell to the action of a drug may perhaps be explained 
by the latter failing to penetrate into its interior, but this is not true in 
the great majority of cases. 

The fields of activity of different drugs vary greatly in extent. One 
may comprise only the terminations of the secretory fibres in the sweat 
glands (agaricin), while another, which affects these in the same way, 
may involve many other terminations in its action (atropine). Most 
poisons, however, while acting on a certain narrow area in small doses, 
extend the limits of their activity when larger quantities are ingested. 
Thus, a poison which acts in small doses on the medulla oblongata 
only, may, when exhibited in larger quantities, involve the spinal cord 
and the brain, and in still greater concentration may affect the heart 
and other organs. No poison is known that acts equally on all organs 
and tissues, but those which have a wide field of operation are often. 



REMOTE, LOCAL, AND GENERAL ACTIOS. 23 

known as protoplasm poisons. These paralyze any form of living mat- 
ter when they are brought in contact with it in sufficient quantity, but 
if they are injected into the blood and thus distributed equally through- 
out the body, they invariably select some special organ as the chief 
seat of their activity. This is exactly parallel to the behavior of chem- 
ical agents in the laboratory. For example, acetate of lead added to 
a solution of a chloride, or of a sulphate, precipitates it, but added to 
a mixture of the two, throws down more of the sulphate than of the 
chloride. Nitrate of silver, on the other hand, precipitates the chloride 
only. Acetate of lead may be compared to the protoplasm poisons, 
nitrate of silver to those with a less extensive field of action. As proto- 
plasm poisons affect a large number of different forms of living matter 
it follows that they alter the nutrition rather than specialized functions. 
Many of them cause irritation ; others are used to destroy or retard the 
growth of microbes and are known as disinfectants or antiseptics. 

REMOTE, LOCAL, AND GENERAL ACTION. 

Drugs change directly only those organs and tissues with which they 
come into immediate contact. But the alteration of one part of the 
organism very often entails that of another to which the drug may not 
have access, or for which it has no special affinity, because impulses are 
transmitted through the nerves, or changes are induced in the circula- 
tion and nutrition. Thus irritation of the skin may alter the rate of 
the pulse by impressions being transmitted by the cutaneous nerves 
and reflected along the inhibitory nerves of the heart. Similarly a 
poison that weakens the heart may induce disorder of the respiration, 
from the circulation being deficient in the medulla oblongata ; and 
depression of the brain ma}^ lessen the oxidation in the muscles, because 
it leads to lessened movement. These secondary changes, which are 
not due to the direct action of the drug on the organs concerned, are 
known as remote or indirect effects. 

The local action of a drug is that induced at the point of application 
before it enters the circulation, the general or systemic action is that due 
to its elective affinity for certain organs to which it is carried by the 
blood. The local effects are very often entirely different in nature 
from the general action, for a drug may act as an irritant at the point 
of application and as a depressant to the brain when it is carried to it 
in the blood. Local effects may be induced wherever the drug can be 
applied — in the skin, the alimentary tract, the respiratory passages, and 
the other mucous membranes. They also occur in the subcutaneous 
tissues when the poison is injected hypodermically, and in any of the 
deeper organs and tissues which can be reached by the needle of the 
syringe. Local remedies may cause irritation, or may protect the sur- 
face from irritation, may depress the sensory end-organs and cause 
local anaesthesia, or lessen secretion, or alter the functions at the point 
of application in many other ways. They may also have remote effects, 
as has been mentioned. Many drugs have only a loeal action, because 



24 INTR OD UCTION. 

they are not absorbed, are absorbed in inactive forms, or are excreted 
or deposited as rapidly as they pass into the circulation, so that enough 
is not present in the blood at any one time to induce general effects. 
On the other hand, many powerful poisons have little or no effect at the 
point of application, but possess an elective affinity only for some 
organ to which they are carried by the circulation. 

THE RELATION BETWEEN CHEMICAL COMPOSITION 
AND PHARMACOLOGICAL ACTION. 

As the effect of drugs on living matter is conceived to be due to a 
chemical reaction between them, it might be inferred that those drugs 
which present a close resemblance in their chemical properties and com- 
position must induce similar changes in the organism. And this is true 
as a general statement, although the relation existing between chemical 
constitution and pharmacological action can be followed only a short 
distance as yet. For example, so many members of the methane series 
of chemistry depress the central nervous system that this may be re- 
garded as a general property of these bodies, just as they possess certain 
general chemical reactions, which distinguish them from the members 
of other chemical series. In the same way, the heavy metals resemble 
each other in their general effects on the organism, just as they react 
similarly to some chemical tests. But whenever an attempt is made to 
follow this relation in detail, the analogy breaks down, because factors 
which it is impossible to deduce from the chemical constitution, make 
themselves felt. Exactly the same thing occurs in chemistry ; for 
example, the heavy metals resemble each other in so many respects that 
it might be inferred that the sulphides would be of the same color, or 
that the chlorides would be equally soluble in water, but experiment 
shows that this is not the case. In the same way they resemble each 
other in many points in their effects in the organism, but it cannot be 
inferred from this that they will have the same effect on any given 
organ or in any given respect. A simple example of the very differ- 
ent effects in the organism of drugs which are closely related chemically, 
is offered by the action of the simpler members of the acetic acid series 
on the sense of smell. For formic, acetic, proprionic, butyric and 
valerianic acids can be easily distinguished by their odors, that is, they 
act differently on the terminations of the olfactory nerves, yet they 
form a homologous series of as closely related members as any chemical 
series can offer. They present certain differences in their chemical 
reactions, of course ; for example they vary considerably in the solu- 
bility of the salts they form with barium and calcium, and it is im- 
possible to explain, or to anticipate these variations from any consider- 
ation of their chemical constitution. If then their reactions with such 
simple and familiar bodies as calcium and barium cannot be anticipated, 
it would seem futile to attempt to foretell their behavior towards the 
infinitely more complex and less known protoplasm of the nerve ter- 
minations. 



CONDITIONS MODIFYING THE EFFECTS OF DRUGS. 25 

A great deal of time and energy has been devoted to an attempt to 
bring the effects in the organism of certain metals (notably the alka- 
lies) into relation with their atomic weights, their valency, and other 
properties, but no results are to be expected from these researches, so 
long as their ordinary chemical reactions can only be formulated to a 
limited extent and imperfectly from these considerations. In particu- 
lar, it seems of little interest to determine their exact relative toxicity, 
since there is no question that they do not all act on the same organs, 
and if one act on the brain and another on the heart, one by its specific 
affinity for an organ and another by inducing physical changes in the 
fluids of the body, these differences are sufficient to nullify any rela- 
tion which they may bear to each other in regard to the exact fatal 
dose. As has been stated, it may be inferred with some probability 
that any substance belonging to certain wide chemical groups will in- 
duce symptoms in the organism resembling in general characters those 
of the other members provided always that it does not contain some 
radicle which renders it inactive, or gives it a more powerful action in 
some other direction. But the details of its action can be ascertained 
only by actual experiment, exactly as the details of its chemical be- 
havior can be known only by performing the necessary reactions ; and 
as there is no prospect of explaining the latter from its constitution at 
the present time, there is still less hope that much advance will be 
made in the near future in formulating the laws governing the details 
of its pharmacological effects. 

CONDITIONS MODIFYING THE EFFECTS OF DRUGS. 

The effects of drugs on the living organism are subject to some modi- 
fications in certain individuals, and under some conditions, which it 
is of importance that the physician should recognize, as the dose has to 
be altered when they are present. One of these is the Size and Weight. 
If the same amount of a poison be distributed through the tissues of 
a large individual as of a small one, less is contained in any given organ 
of the former and less effect is therefore observed. This has been 
ascertained chiefly in animal experiment, in which the effects of 
drugs can be estimated much more exactly than in man, but it un- 
doubtedly holds good for human beings also. Very large individ- 
uals, then, require a somewhat larger dose than ordinary persons, 
while in treating individuals of small stature, the dose has to be 
reduced. 

The Age of the patient has also to be taken into account in prescrib- 
ing. Children ought to receive much smaller doses than adults. The 
more powerful action of drugs in children is due in part to their smaller 
size, in part to the more active growth of certain tissues and to the less 
complete development of others, such as the central nervous system. 
The dose for a child is generally calculated according t<> Young's 
formula, in which a fraction obtained by dividing the age by the age + 
12, is taken as the proportion of the adult dose required. Thus for ■ 



26 INTRODUCTION. 

child of four years, the dose would be ( j -^ = J J of the adult dose, 

for one of one year ( ,19 = ) tV °f the adult dose. According to 

another less used formula, the dose for a child is ascertained by divid- 
ing the adult dose by 20, and multiplying the result by the age. 
Brunton suggests dividing the dose by 25 and multiplying the result 
by the age at the next birthday. These formulae are not, however, inva- 
riably safe guides to follow in prescribing. For example, the narcotics,, 
particularly opium and its preparations, must be given during the first 
years of life in much smaller quantities than are indicated by Young's 
rule, while alcohol may be administered in comparatively large doses. 

The usual dose advised has to be modified for children then, and 
may be taken as that suitable from 20-60 years. After this age is 
passed, it is again reduced somewhat, so that from 70-80 about f of 
the adult dose is advised, and after 85 it may be reduced to J. There 
are exceptions to this rule also, large doses of the purgatives, for ex- 
ample, being often necessary in old people. 

Sex. — Women generally require somewhat smaller doses than men, 
because of their smaller size, and it is often stated, because their tissues 
react more strongly to some drugs, though this has not yet been satis- 
factorily established. 

Temporary conditions also influence the activity of drugs. Thus 
after a meal, a poison is absorbed more slowly from the stomach than 
when it is taken fasting, and any local irritant action is also less 
marked, because the drug is diluted by the contents of the stomach. 
Irritation of the stomach and intestine may also modify the effects of 
drugs ; thus in some forms of dyspepsia the absorption is slower than 
usual and little effect may be induced by the ordinary dose, while irri- 
tant drugs naturally cause more disturbance of the digestion in these 
cases. On the other hand, a slight congestion of the stomach and bowel 
tends to promote absorption, and it has been found that more of a 
heavy metal is absorbed when it causes some destruction of the mucous 
membrane than when it is given in smaller quantities. Vomiting 
and diarrhoea, of course, tend to lessen the action of drugs by re- 
moving them rapidly from the alimentary canal. 

During pregnancy, purgatives have to be used with great care, be- 
cause they induce congestion of the pelvis, and may lead to abortion. 
Drugs acting on the uterus, or inducing a marked fall of blood pres- 
sure, are to be avoided because the former may cause the evacuation of 
the uterine contents, while the latter may lead to asphyxia of the foetus. 
Many drugs pass from the mother to the child, and this is to be borne 
in mind, as quantities which are insufficient to poison the former may 
have more serious effects on the latter. During lactation, it is impor- 
tant to remember that active bodies may be excreted in the milk, and 
may either act on the child or render the milk distasteful to it. In 
menstruation, purgatives are to be avoided, as they tend to increase 



CONDITIONS MODIFYING THE EFFECTS OF DRUGS. 'J 7 

the flow, and all very active drugs are to be used with care or aban- 
doned temporarily. 

The Time of Administration has also some influence on the effects of 
drugs. The body is generally more resistant in the morning than in 
the evening, especially in the case of narcotic drugs ; thus a dose of a 
soporific which may have little or no effect in the early hours, induces 
sound sleep when given in the evening, because the brain is already 
fatigued and depressed. 

Idiosyncrasy is used to denote an unusual effect for which no expla- 
nation can be found. Some persons react more readily than usual to 
the ordinary dose, while in other instances a much larger quantity can 
be taken without any effect. Others, again, show symptoms which are 
entirely different from, and which may, in fact, be diametrically opposite 
to those ordinarily observed. These idiosyncrasies are naturally more 
frequently seen, aud are better known when they arise from widely 
used drugs. Thus the modern antipyretics have so often induced ab- 
normal symptoms that these are well known, but it is not improbable 
that if other drugs had been used, or rather abused, to the same extent, 
they would be found to induce unusual reactions in an equally large 
number of individuals. An idiosyncrasy, as has been said, cannot be 
explained in the present state of knowledge, but some conditions which 
have been termed idiosyncrasies are probably due to abnormally rapid, 
or to retarded absorption or excretion. Idiosyncrasies are not con- 
fined to human beings, for not infrequently one animal reacts quite 
differently from others of the same species. 

As has been mentioned, one form of idiosyncrasy consists in the fail- 
ure of the individual to react to the ordinary dose of a drug. This is 
known as Tolerance, and this particular form of idiosyncrasy may be 
termed congenital tolerance. Certain species of animals tolerate quan- 
tities of drugs which would be fatal to others of the same size. In 
fact, so frequently is this the case that it is impossible to determine the 
fatal dose of any drug on an animal from experiments performed upon 
others of a different species, even though it be nearly related. One of 
the most remarkable examples of this form of tolerance is met with in 
the hedgehog, which resists large doses of many very active poisons. 
Another well-known example is the tolerance of the rabbit of large 
quantities of atropine. 

A form of tolerance which is a matter of everyday observation is that 
induced by the prolonged use of a drug, which has been called acquired 
tolerance, or mithridatism, from the belief that Mithridates protected 
himself in this way from the danger of poisoning. The most familiar 
example of this form of tolerance is that acquired for tobacco (nicotine) ; 
the first cigar often induces violent poisoning, but if a habit be formed, 
large amounts of nicotine may be absorbed without apparent harm. 
not because the absorption is retarded, or the excretion is accelerated, 
but because the tissues become accustomed to the presence of small 
quantities of nicotine, and thus fail to react to it. Nicotine, in tact, 
becomes a normal constituent of the tissues. This tolerance i> entirely 



■28 INTRODUCTION. 

different from the immunity induced by toxalbumins (see Ricin), and it 
is desirable that the two terms should be kept distinct. Very often 
while tolerance for a poison is established in certain tissues, others 
suffer from the prolonged use of excessive quantities ; for example, 
although the seasoned smoker does not suffer from the nausea and 
vomiting which followed his first essay, other organs may in course of 
time become involved, such as the heart or the eye. It is to be noted 
that tolerance is soon lost if the drug be discontinued for some time. 
This is of great importance in cases of opium-eating, for a person who 
has taken opium for a long time acquires a tolerance for the drug, so 
that sometimes enormous quantities are required in order to induce 
the ordinary effects, but if the habit be discontinued for some time 
the tolerance is lost, and a dose which would formerly have had little 
effect may now induce dangerous poisoning. The prolonged use of 
one drug may establish tolerance for others of the same class. Thus 
chronic drunkards are not influenced by large quantities of alcohol, 
and are also more resistant to the action of chloroform than ordinary 
persons, this being due to the fact that chloroform and alcohol act on 
the same nerve cell in the same direction, and probably induce -the 
same changes in the protoplasm. 

The Cumulative Effect of drugs is another phenomenon caused by their 
prolonged ingestion. Small doses of certain drugs taken repeatedly 
for some time eventually cause symptoms which are much more marked 
than those caused by a single small dose. In many instances this 
seems due to the accumulation of considerable quantities in the tissues. 
The absorption may be more rapid than the excretion, and each new 
dose thus adds to the total quantity in the blood and organs more than 
is lost in the same time by excretion. The classical example of cumu- 
lative action is that of digitalis, but it is much more frequently induced 
by such drugs as mercury, arsenic, or the iodides, for the so-called 
chronic poisoning induced by these is really an example of cumulative 
action. It has been suggested that cumulative action is not really due 
to the accumulation of the drug in the tissues, but to a summation of 
a prolonged series of effects of the same kind ; but although the increase 
of the drug in the organs has not been proved in all instances, it seems 
probable that this is the explanation in the great majority of cases, 
perhaps in all. Cumulative action may occur along with tolerance, as 
has been stated. Thus the tolerance of certain tissues for nicotine does 
not protect others from the effects of the abuse of tobacco. 

Synergists. — The presence of another drug having the same effects 
in the body often increases the action of a remedy to an unexpected 
extent. This is the ground for the prescription of several remedies 
acting in the same way. 1 For example, several purgatives prescribed 
together often act more efficiently than any one given in quantity equal 
to all of them. It is quite impossible to explain this except by 
assuming that, although all are alike in their chief features, they 
differ in the details of their reactions, so that parts of the alimentary 

1 The less important ones are sometimes termed adjuvants. 



CONDITIONS MODIFYING THE EFFECTS OF DRUGS. 29 

canal which might escape one are affected by another, and the mixture 
thus acts more universally than any one of the components Jt must 
be added that, although the greater efficiency of the mixture is attested 
by the general belief of physicians, no very satisfactory researches on 
the subject have been carried out as yet. 

On the other hand, a drug may fail to elicit any symptoms if an 
antagonistic substance be present in the body. Thus in cases where a 
powerful nervous depressant, such as chloroform, has been inhaled, 
strychnine may have little or no effect on the spinal cord in doses 
which would normally increase the reflexes to a marked extent. In the 
same way, if the terminations of the inhibitory fibres of the heart arc 
paralyzed by atropine, a poison which normally slows the heart by 
stimulating these terminations will have no such effect except in very 
much larger doses. 

Similar modifications of the effects of drugs may be induced by poi- 
sons induced by pathological changes in the tissues, or by an unusual 
state of irritation or of depression of the tissues themselves. For ex- 
ample, in hot weather and in tropical climates, purgatives are found 
much more efficient than in colder climates, either because there is 
some poison which acts along with the purgative, or because the mucous 
membrane is more irritable than usual. That some such factor is 
present in these conditions, is shown by the frequent occurrence of 
diarrhoea without the use of drugs. 

Similarly when an antagonistic poison is formed in the tissues in the 
course of a disease, a drug may have little or no effect ; so that if the 
inhibitory cardiac terminations are paralyzed by disease, the heart 
cannot be slowed by muscarine or digitalis. 

Pathological conditions very often modify the effects of drugs to a 
very considerable extent, and in a way which cannot be explained at 
present. For example, the antipyretics reduce the temperature in 
fever, but have no effect on it in health ; the bromides lessen the con- 
vulsions in epilepsy, but have much less effect in depressing the brain 
in normal persons. The question may therefore be raised whether 
the examination of the effects of drugs in normal animals is of much 
value in indicating their therapeutic action. But in reply it may be 
said that in a large number of instances drugs are given, not in order 
to act upon the diseased tissues, but upon healthy ones. The object of 
the therapeutist is very generally not to restore the diseased tissue, 
but to relieve it from work, and to allow it rest so as to promote its 
restoration by nature. For instance, in disease of the cardiac valves, 
drugs are given not with the object of restoring their integrity, but to 
act upon the healthy heart muscle, and to obviate the disturbance 
of the circulation which is caused by the destruction of the valves. I n 
inflammation of the kidneys, the physician seldom attempts to reduce 
the inflammation by the action of drugs on the cells involved, but 
confines his attention to removing by other channels the product- of 
tissue waste, which would normally be excreted by the kidney. 
that in most instances drugs are given to act on normal tissues, or on 



30 INTRODUCTION. 

tissues which are so little affected by disease that they react to reme- 
dies in the same way as the normal. In other cases in which the 
remedy acts on the cause of the disease or on the diseased tissue, its 
introduction is due to clinical experience only. Thus quinine destroys 
the organism of malarial fever, but this could never have been antici- 
pated from its action on the normal tissues, and could only be discov- 
ered by experiments on the organism, or rather by experiments on 
persons suffering from the disease, as the organism has been recog- 
nized only of late years. 

METHODS OF ADMINISTRATION. 

The effect of a remedy is often determined very largely by the 
method in which it is administered. As regards the local action, this 
is sufficiently obvious, for an irritant applied to the skin could scarcely 
be expected to cause the same symptoms as if it were applied to the 
stomach and intestine. But the same holds true for the general action 
in most instances, because some tissues and organs absorb much more 
rapidly than others, and a larger quantity of the drug therefore passes 
through them into the blood in a given time. Thus, if a poison which 
is absorbed slowly be rapidly excreted, so little of it may exist in the 
blood and tissues at any given time that no effects are induced, while 
if it be rapidly absorbed, the same dose can exert some action before it 
is excreted. 

Drugs are applied for their Local Action to the skin, to the mucous 
membranes of the alimentary, respiratory, and genito-urinary tracts, 
and to the conjunctiva and cornea. Not infrequently they are injected 
by means of the hypodermic needle into the subcutaneous tissues for 
their local effects, and the attempt is continually being renewed to 
treat even the deeper tissues and organs locally by the injection of 
remedies into them. The objects of local medication are very diverse, 
and can be treated of only in connection with the individual drugs. 
The methods of application are also so numerous that only a few of the 
chief can be mentioned. Drugs intended for application to the skin 
are often formed into salves or ointments (unguenta) by mixing them 
with oily or fatty substances, which adhere to the skin and do not 
dry up, and which in addition to serving as a means of applying an 
active substance, protect the surface from the air and from irritation. 
Other preparations for application to the skin, such as the plasters 
(emplastra), resemble the ointments in their general characters, but 
also give mechanical support, and bind surfaces together from their 
being spread on paper or cloth, which thus serves as a flexible splint. 
The collodions and cerates resemble the plasters, the oleates the oint- 
ments. In addition to these special preparations, drugs may be ap- 
plied to the skin in solutions, or as powders, or solid masses may be 
used to cauterize it. 

The methods of applying drugs to the alimentary tract and to the 
lungs for their local action are for the most part similar to those used 



METHODS OF ADMINISTRATION. 31 

for drugs which are intended to be absorbed. The mouth and throat 
may be washed out. with solutions, which are gargled (gargarismata), 
or may be treated with powders, or lozenges (trochisci), which are 
slowly dissolved and thus permit of a more prolonged and constant 
action in the mouth than is possible if the drug be swallowed imme- 
diately. The nose may be washed out with solutions of active drugs, 
or powders may be drawn into the nostrils as snuffs ; the latter often 
cause sneezing, and are sometimes known as sternutatories, or errhines. 
The larynx may be treated locally by the application of powders or 
of very small quantities of fluids by means of the laryngoscopic mirror 
and probe. Solutions are generally used for application to the con- 
junctiva, but a more permanent effect can often be obtained from the 
use of ointments or powders Avhich are less liable to be washed away 
by the tears. The urethra, vagina and uterus are treated by the in- 
jection of solutions, or by ointments and powders. Bougies, which 
are occasionally advised, are formed by incorporating an active drug in 
some substance which is solid at ordinary temperatures, but melts 
when introduced into the organ and allows the drug to come into con- 
tact with the surface. The rectum may similarly be treated by the in- 
jection of drugs in solution or suspension (enemata), or by the use of 
suppositories. Drugs are not infrequently applied by the rectum in 
order to elicit their action after absorption, but much oftener for their 
local action on the bowel. Enemata may be either large (a pint or 
more) or small (2-5 c.c, J-l fl. dr.). The large enemata are used 
either to wash out the intestines, and may then contain an antiseptic 
or astringent, or to induce peristalsis and evacuation of the bowel, 
when they are made up of water with or without soap or other slightly 
irritant substances. The small enemata are used chiefly to induce 
evacuation, and contain more irritant substances, such as glycerin 
alone or along with some more active body (see uses of the vegetable 
purgatives). The suppositories are formed of cacao-butter, which is 
solid at room temperatures, but melts at the temperature of the rectum. 

All the visible mucous membranes may also be cauterized by the 
application of a solid rod of a corrosive for a short time. 

Drugs whose General Action is to be elicited after their absorption 
are given by the mouth, except when some special character in them or in 
the disease renders some other method preferable. They may be given 
by the mouth in solution in water, alcohol, oils, or other more or Less 
indifferent bodies. The disagreeable taste of many remedies, however, 
often precludes this method, and these may be ordered in the form of 
pills, or in capsules, which are formed of gelatin or similar substances and 
are dissolved in the stomach and intestines. Very often the disagree- 
able taste may be concealed by the addition of sugar, or of some st rongly 
tasting but agreeable body such as a volatile oil. Insoluble drugs may 
be given as powders, as they have little or no taste. Powders are also 
used as a means of administering soluble drugs, if they have not a (Un- 
agreeable taste and have no marked local action, but very deliquescent 
drugs should not be given in this form. Insoluble drugs are sometimes 



32 INTRODUCTION. 

ordered in suspension in mucilaginous fluids ; and oils, which are dis- 
tasteful to many people, may be given mixed with water and gums 
(emulsions). 

The rate of absorption from the alimentary canal varies greatly 
with different drugs and also with the form in which they are adminis- 
tered. The first point will be treated of in connection with the indi- 
vidual drugs. As regards the second, it may be stated that drugs are 
more rapidly absorbed when they are swallowed in solution, and that 
when much inert and insoluble matter is associated with them, their 
absorption is much retarded. Thus, common salt passes more rapidly 
into the blood when it is dissolved before being taken than when it is 
swallowed dry, and morphine is absorbed much more quickly when it is 
administered pure than when, as in opium, it is mixed with a mass of 
gums and other bodies. This fact is taken advantage of in practice by 
giving drugs in solution when rapid absorption is desirable, and by giv- 
ing less pure forms when the local action on the stomach and bowel 
is to be elicited. The more concentrated the solution, the greater is 
the irritant action on the stomach, and thus where irritation of the 
stomach is desired, either the solid drug or a strong solution is given ; 
but as a general rule the local action on the stomach is to be avoided, and 
drugs are therefore ordered in as dilute solution as is possible without 
increasing the bulk to too great an extent. It is to be noted that 
drugs which are insoluble in the test-tube may be rendered soluble by 
the action of the gastric and intestinal juices, while many which are 
given in solution, are thrown down in the stomach in the form of 
insoluble albuminates. 

The great mass of drugs absorbed from the stomach and intestine 
is carried to the liver before reaching the general circulation, and this 
is of great importance in determining their effects in the body, as some 
of them are retained in that organ, and are either entirely destroyed or 
escape so slowly that they have no perceptible effect. 

Another important method of administering drugs for their general 
action and also for their local effects is by inhalation into the lungs.. 
Only volatile drugs can be used thus for their general action. They 
are absorbed very rapidly owing to the extensive surface to which they 
are applied, and also because volatile substances penetrate the tissues 
more readily than others. The best examples of inhalation are offered 
by the general anaesthetics, chloroform and ether. Most substances 
absorbed by the lungs are also excreted by them, and this leads to an 
important practical point in regard to the anaesthetics. For the passage 
of gases or vapors through the lining epithelium of the alveoli depends 
in most instances 1 upon their partial pressure, that is, upon their con- 
centration in the air and blood respectively. Accordingly, when the air 
contains more chloroform vapor than the blood, the anaesthetic passes 
into the blood, but as soon as the condition is reversed, and the blood 
contains more chloroform than the air of the alveoli, it commences to* 

1 Such gases as oxygen and carbon monoxide, which form chemical combinations , 
with the haemoglobin, are of course exceptions. 



METHODS OF ADMINISTRATION. 33 

pass backwards. The more concentrated the vapor inhaled, the more 
chloroform is contained in the cubic centimeter of blood, and the greater 
is the action on the nervous centres and the heart. 

Less volatile substances are sometimes inhaled into the lungs for 
their local action, and even non-volatile bodies suspended in a spray 
of vapor may be thrown into the respiratory passages, but it may be 
questioned whether these last really reach the alveoli except in trace-. 

Drugs are also applied to the skin in order to elicit their general 
action. Volatile bodies are certainly absorbed by it, although much 
more slowly than by the lungs or by the stomach and intestine. Solu- 
tions in water of non-volatile drugs are not absorbed from the skin, but 
solutions of certain remedies in alcohol, oils, fats, ether, and some other 
substances which are capable of dissolving or mixing with the fatty 
covering of the skin, are absorbed fairly rapidly if they are rubbed in 
thoroughly. This method of application (inunction) has been used 
chiefly for the absorption of mercury, as the local action on the stomach 
and bowel is thus avoided. (See Mercury.) Alkaloids do not appear 
to be absorbed by the skin even when dissolved in oils or alcohol. An 
entirely obsolete method of application is the endermic, in which the 
epidermis was removed by a blister, and the remedy then applied to 
the exposed corium. 

The hypodermic method is of comparatively recent origin, but is 
being more widely used every year. In it drugs are injected through 
a fine hollow needle into the subcutaneous, or, in the case of more 
irritant substances, into the muscular tissue, where they meet with 
fewer sensory nerves. Absorption occurs more rapidly than when 
drugs are given by the mouth, the local action on the alimentary 
canal is avoided, and the physician is more certain that the whole 
of the remedy is effective, provided it is soluble and is not pre- 
cipitated at the point of injection. At the same time, the method 
has certain drawbacks, the chief of which are the pain of the injec- 
tion and the danger of injecting a powerful remedy into one of the 
subcutaneous veins. Hypodermic injections should be made only 
by the physician or trained attendant, for incalculable injury has 
been done by entrusting patients with the syringe, particularly for the 
injection of morphine and cocaine. The needle and syringe ought to 
be disinfected, and the substance injected should be aseptic, and this 
renders the method inconvenient. As a general rule, solutions in 
water or in dilute alcohol are used for injection, but the insoluble 
salts of mercury have also been injected, suspended in oil (see Mer- 
cury). Irritant drugs are to be avoided as far as possible, as they 
cause great pain, swelling and sometimes suppuration, even when the 
injection has been carried out aseptically. Hypodermic injection is used 
very largely to elicit the general action of a remedy, but also for 
the local effects, as when cocaine is injected in order to produce local 
anaesthesia. Solutions of inert bodies have also some anaesthetic action, 
probably owing to their mechanical action on the sensory nerve libit-. 
As the absorption from the subcutaneous tissues is so much move rapid 
3 



34 INTRODUCTION. 

than that from the stomach and intestine, when the drug is in perfect 
solution the dose has to be reduced. As a general rule, about one- 
half of the ordinary amount is sufficient. 

Deeper injections are sometimes made for their local action on the 
organs. Thus, antiseptics have been injected into lung cavities, caustics 
have been injected into tumors, and direct applications have been made 
to the nerves in sciatica and other similar disorders. 

Intravenous injection is the most certain method of bringing drugs 
into the circulation and tissues, and is at the same time the most rapid. 
It is, therefore, very largely used in experiments on animals, but 
has generally been considered too dangerous for therapeutic purposes 
in man. Baccelli has, however, recommended it highly in recent years 
in cases of emergency, in which the immediate action of a remedy is 
required. In pernicious malaria, and in syphilis when an important 
organ is threatened, he has injected small quantities of quinine and 
mercury with great success. The dose must be very much smaller 
than that employed by the mouth, but it is impossible as yet to state 
exactly what fraction will induce the same effects. 

Drugs are occasionally applied by the rectum for their general action, 
as has been mentioned. The local effects on the stomach are avoided 
by this method, and morphine and opium are, therefore, not infrequently 
administered thus. The rate of absorption from the rectum as com- 
pared with that from the stomach and bowel is still a disputed point, 
and some physicians recommend that the dose be reduced to three- 
fourths, while others recommend one and one-half times that given by 
the mouth. 

Drugs are not administered by the other mucous membranes for their 
general effects, but it must not be forgotten that symptoms may arise 
from their application to them for their local action. Similarly, drugs 
applied as dressings to wounds or abrasiojish&ve very often given rise to 
severe or fatal poisoning from being absorbed into the blood and tissues. 

THE CHEMICAL CHARACTERS OF DRUGS. 

An enormous number of substances induce changes in the living 
organism, and have, therefore, to be recognized in pharmacological 
treatises. Many of them are comparatively simple chemical com- 
pounds, and require no general description here, but less attention is 
paid in ordinary chemical textbooks to certain groups of active poisons, 
and some note must be taken of their general properties. 

In the inorganic materia medica are found many salts, bases, and 
acids, and a few uncombined elements, such as mercury and phosphorus. 

Organic chemistry offers a large and ever-increasing number of arti- 
ficial compounds which belong to almost every one of the divisions 
recognized in chemistry. The hydrocarbons, alcohols, ethers, phenols, 
ketones, aldehydes, acids, and many others, contribute active agents, 
and in fact most of them are represented by one or more members in 
therapeutics. They may all be regarded as sufficiently known by stu- 



THE CHEMICAL CHARACTERS OF DRUGS. 35 

dents who are prepared to study pharmacology with profit, but some 
substances, obtained chiefly from plants, require further mention. 

The first group of these is formed by the Alkaloids, which are 
substituted ammonias, and have a more or less strongly alkaline re- 
action, so that they are often known as the vegetable bases. They 
contain carbon, hydrogen, nitrogen, and, as a general rule, oxygen, 
although some of them, such as coniine, are devoid of it. Like am- 
monia, they combine with acids readily without eliminating hydrogen, 
and the salts thus formed resemble those of ammonia in many respects, 
among others in being thrown out of combination by the fixed alkalies. 
The term alkaloid is often restricted to compounds of pyridine and 
quinoline, and this is convenient in treating them from a chemical 
point of view. But the pharmacological action of some of the substi- 
tuted ammonias of the methane series has so much in common with 
that of the pyridine bodies that it is impossible to maintain this narrow 
definition. Most of the vegetable alkaloids whose constitution is 
known are derived from pyridine, quinoline and isoquinoline by the 
addition of hydrogen, and generally by the substitution of one or more 
of the hydrogen atoms by side chains of greater or less complexity. 

CH CH CH HC CH 

HC/ \.CH Hc/\/\cH Hc/X^XcH 

cl A Jc 



JcH Hcl A JcH HC 



\/ CH HC \^\/ CH HC \/\/ N 

N CH N CH CH 

Pyridine. Quinoline. Isoquinoline. 

In these the nitrogen takes the place of one of the carbons in benzol 
and naphthalin respectively. In others the nitrogen is attached to 
radicles belonging to the methane or open-chain series, as in CH(OH) 2 
— CH 2 — N(CH 3 ) 3 OH, which is generally regarded as the formula of 
muscarine. A third series of bodies, which may be regarded as alka- 
loids, although they differ from the others in many respects, are de- 
rivatives of aniline, and are artificial products. 

CH 
HC/ \C— NH 2 
Hcl JcH 

CH 
Aniline. 

These aniline derivatives bear some relation to the vegetable bases 
in their action, but are equally or more nearly related to the benzol 
series so that they may be regarded as connecting links between these 
two classes of bodies. 

Some of the vegetable alkaloids have been formed synthetically in 
the laboratory, and the constitution of some of the others is perfectly 
well known, but many of them have not yet been isolated, and there 
are probably others whose existence is not even suspected. These vege- 
table alkaloids occur in almost all parts of plants, although they are 



36 INTRODUCTION. 

found in greatest abundance in the seeds and roots. The same alka- 
loid is often found in most of the plants of a genus, or it may occur in 
one or two species of a genus and in other plants which are in no way 
related. Very often more than one alkaloid is found in a plant, and 
these may differ entirely in their action on animals, although not in- 
frequently all the alkaloids of a plant resemble each other in their 
effects. The alkaloids are found almost exclusively in dicotyledonous 
plants, only one or two being known to exist in the monocotyledons. 
Muscarine is found in the fungi, and quite recently alkaloids have 
been isolated from the suprarenal capsule of animals and from the skin 
of the salamander. 

The alkaloids are very often only slightly soluble in water, but 
form salts which are generally more soluble. Many of the bases are 
dissolved in ether, chloroform and amyl alcohol, while the salts are in- 
soluble in these. Both bases and salts are generally fairly soluble in 
alcohol. The alkaloids are precipitated from solution by a large num- 
ber of reagents, of which the most important are the chlorides of 
platinum and of gold, tannic acid, phosphotungstic and phosphomo- 
lybdic acid, the double ic™ks of potassium and mercury, and of po- 
tassium and cadmium, and Tomne held in solution in water by potassic 
iodide. The hydrates and carbonates of the alkalies and the alkaline 
earths precipitate the alkaloids from solutions of the salts in water, a 
point of some importance in prescribing these bodies. In cases of 
poisoning when the alkaloid has been taken by the mouth, it may be 
precipitated in the stomach by dilute alkalies or better by tannin solu- 
tions. The poison should then be removed by inducing vomiting or 
by washing out the stomach with the stomach tube. 

Another important class of vegetable poison is formed by the Glu- 
cosides (glycosides), or saccharides, which are esters (compound ethers) 
composed of sugars and hydroxyl substances, and which liberate 
sugar when they are heated with acids, or sometimes with alkalies, or 
when certain unorganized ferments act on them. The sugar formed in 
this way is often glucose, but not invariably so; the other decompo- 
sition products have been identified only in a few instances. Many of 
the glucosides contain only carbon, hydrogen and oxygen, a few have 
nitrogen in addition and one or two sulphur. In some instances the 
remainder, after the sugar is split off, is an alkaloid, e. g., solanidine. 
Glucosides differ greatly in their solubility in water and alcohol ; com- 
paratively few of them are soluble in ether. Some of the glucosides 
are powerful poisons, others have little or no action. 

Resins, an ill-defined group, are found in many plants, and are 
characterized by their smooth, shining fracture, and by their insolubility 
in water and solubility in ether, chloroform, volatile oils, benzol and, in 
many cases, in alcohol. They seem to be formed in plants by the oxi- 
dation of volatile oils, and are often acid or anhydride in character, 
while others are apparently alcohols or esters. The resins are almost 
invariably composed of several different substances mixed together. 
Many of the resins are local irritants, and some are poisonous in com- 



PHARMACOPCEIAS AND PHABMACOPCEIAL PREPARATIONS. 37 

paratively small quantity from the powerful action they exert on the 
intestine. 

Oleoresins are solutions of resins in ethereal oils, which lend them a 
characteristic odor and taste. 

The term 'Balsam' is often used as synonymous with oleoresin, 
but most writers restrict it to those oleoresins which contain ben- 
zoic and cinnamic acid along with other constituents. (See Benzoic 
Acid.) 

Gumresins are mixtures of resins and gums, generally containing gome 
volatile oils. They are insoluble in water, but the resin is suspended 
in it by the gum. On the other hand, the resin is dissolved by alcohol, 
while the gum remains insoluble. 

Gums are amorphous, transparent substances, composed of carbohy- 
drates of the formula C 6 H 10 O 5 and are thus nearly related to cellu- 
lose and starch. Some of them are soluble in water, while others 
merely swell to a jelly in it; they are insoluble in alcohol. They 
generally occur in plants in combination with calcium, magnesium or 
potassium ; they have no poisonous action, but form a protective cover- 
ing for irritated surfaces, and are largely used to suspend in water sub- 
stances which are insoluble in it, such as resins and oils. 

Volatile oils occur in plants in large numbers. (See page 60.) 

Many Acids which are of pharmacological and therapeutic interest 
are obtained from plants, but it is unnecessary to enter into a descrip- 
tion of their properties here. 

Fats and oils, sugars, starch, proteids, coloring matter, ferments and 
other bodies which occur in plants, and are contained in many of the 
preparations used in therapeutics, are not generally possessed of any 
action of importance. Those which are active in the body will be 
described individually. 

Finally many of the active principles of plants are entirely unknown 
or have been only partially examined. Among these are a number of 
substances which have little in common except their bitter taste and 
which are known as Bitters. 



THE PHARMACOPCEIAS AND PHARMACOPEIA! 
PREPARATIONS. 

Almost all governments have found it necessary to regulate the 
preparation of drugs used in therapeutics, and for this purpose issue at 
intervals codes of instructions defining the characters of the drugs and 
giving the exact formulae according to which they are to be prepared 
for use. In the United States, where the government has not un- 
dertaken this as yet, a code has been prepared by a voluntary asso- 
ciation of physicians and pharmacists. These codes are known as 
Pharmacopoeias, and some differences exist between those of different 
states, although the most important drugs are found in all of them. 
All the drugs used in therapeutics are not found in the pharmacopoeias, 
for these are iseued only at intervals of several years, and in the mean- 



38 INTRODUCTION. 

time large numbers of remedies are introduced, used for a few months, 
and pass into oblivion. Even when a drug maintains its position for 
many years, and promises to be a lasting addition to therapeutics, it 
often fails to be admitted to the official code, while others of older 
standing, which are comparatively seldom used, and which might be 
omitted without loss, are kept on the list. This conservative tendency 
of the compilers of the pharmacopoeias has its disadvantages, but at any 
rate tends to withhold official sanction from the innumerable ephemeral 
products of chemical industry. The official definition of therapeutic 
substances is of advantage to both physician and pharmacist, as it 
assures the former that the drug he prescribes will have a uniform 
quality, wherever in the country it is dispensed, while the pharmacist 
is saved from the continual preparation of remedies in different forms, 
by their being prescribed in one recognized strength. 

The pharmacopoeias contain a large number of pure substances such 
as salts, acids, bases, alkaloids, and these require no further description. 
On the other hand, many of the drugs are given in an impure form, 
either because the active principle is unknown, or because its isolation 
is attended with difficulty and expense. Thus many of the vegetable 
remedies are presented in the pharmacopoeias as solutions or solids which 
contain not only the active principle but gums, sugars, coloring matter, 
and many other impurities. These are provided in different forms to 
allow of variation in their administration. In addition, the pharma- 
copoeias contain a number of official prescriptions, that is, mixtures 
of active substances in such proportions as are ordinarily prescribed. 
These are generally designated by the addition of compound (compo- 
situs) to the name of the chief ingredient. Most pharmacopoeias 
continue to use Latin in the titles of the drugs, and this is not due to 
mere pedantry or conservatism, as is' often stated. For the popular 
name of a drug is often used for several different substances, as, for 
example, hellebore, while the Latin name in a prescription indicates 
that drug which is known by the term in the pharmacopoeia. In the 
same way it is found necessary to maintain Latin terms in botany and 
zoology in order to define accurately the species. 

Many crude or unprepared drugs are found in the pharmacopoeias, 
such as leaves, roots, flowers, or even whole plants. These are used 
chiefly for the preparation of other more readily applicable remedies, 
but are sometimes prescribed as powders or in pills. 

The following preparations l are official : 

a. Aqueous Preparations. 

Aquae, medicated waters, generally contain only traces of some volatile 
substance, such as an ethereal oil or chloroform, in solution in water, and 
these are used in prescriptions as more agreeable to the taste and smell than 
pure water but have no further effect. In the U. S. P. the solutions of 

1 The student is advised to omit the following list for the present, and to refer to it 
only as he takes up the preparations of the individual drugs. Most of these prepara- 
tions are found in both pharmacopoeias. Those which occur only in the British are indi- 
cated by B. P. , while those which are confined to the United States are marked U. S. P. 



PHARMAC0PCE1AS AND PHARMACOPCEIAL PREPARATIONS. 39 

chlorine, ammonia and hydrogen peroxide are also included under aqua-, but 

these are used only to elicit the specific effects of these drugs and are | 

ful poisons. In the B. P. these strong solutions are included in the liquores. 

Liquores (U. S. P.) are solutions in water of soluble substances which are 
not volatile. The official solutions of powerful poisons are often one per 
cent, in strength. 

Liquores (B. P.) are solutions in the widest sense, in water, alcohol, or 
other fluids. The dissolved substance may be volatile or non-volatile. The 
"concentrated solutions" (B. P., Liquores Concentrati) are not, as might be 
supposed, condensed by evaporation. They resemble infusions and decoc- 
tions in most respects. 

Decocta, or decoctions, are impure solutions of vegetable principles, which 
are obtained by boiling parts of plants in water. 

Infusa, or infusions, are solutions obtained by soaking parts of plants in 
water, which may be hot or cold, but is not kept boiling. Infusions and 
decoctions are weak preparations and decompose rapidly so that they are 
used only when recently prepared. 

Misturse (U. S. P.), or mixtures, are preparations in which substance- in- 
soluble in water are suspended in it by means of gums or similar viscid sub- 
stances. 

Misturse (B. P.) include a number of preparations in which insoluble bodies 
are suspended in water by means of gums or syrup, but one mixture contains 
only soluble bodies. 

Emulsa (U. S. P.), emulsions, are formed by suspending oils in water by 
means of gums or other viscid bodies. The B. P. contains no official emul- 
sions, the corresponding preparations being known as misturse. 

Mucilagines, mucilages, are solutions in water of gums, starch, and sim- 
ilar bodies. 

Syrupi, syrups, are strong solutions of sugar in water, which may be used 
alone, or may be impregnated with more active bodies. Similar preparations 
formed with honey instead of syrup (sometimes known as mellita) are official. 
as Mel Rosse (U. S. P.), Mel Boracis (B. P.). A solution of honey and acetic 
acid is known as oxymel in the B. P. (Oxymel Scillse). 

Lotiones (B. P.), lotions, or washes. This term is used to designate two 
preparations of mercury, the black and yellow wash. 

b. Alcoholic Preparations. 

It is to be noted that in these preparations the menstruum (alcohol) is not 
an indifferent body as in the aqueous preparations ; the effects of some of 
this class are undoubtedly due rather to the alcohol than to the dissolved 
substances. 

Spiritus, spirits, are solutions of volatile bodies in alcohol, and often owe 
their chief action to the solvent and not to the drug contained in it. 

Elixiria (U. S. P.), elixirs, differ from spirits chiefly in containing sugars. 
which are added in order to give them taste. 

Tincturse, tinctures, are solutions in alcohol of medicinal substances, which 
are generally formed by soaking parts of plants in it. They contain both volatile 
and non-volatile ingredients, but the latter are generally the more import ant 

Extracta Fluida (U. S. P.), Extracta Liquida (B. P.), fluid extracts, are 
prepared from plants by forming solutions in water or more frequently in 
alcohol, and evaporating them until the solutions contain as many cubic 
centimeters as the original crude drugs weighed in grammes: that is the 
volume of the fluid extract corresponds to the weight of the crude drug. 

The tinctures and fluid extracts are the most commonly used liquid 
preparations, and most of the important drugs are prepared In one or both 
of these forms. 

Vina, medicated wines, are solutions of active substances in wine or in 
dilute alcohol. 



40 INTRODUCTION. 

Succi (B. P.), the juices of fresh green plants, obtained by pressure. Some 
alcohol is added to preserve them from putrefaction. 

c. Other Fluid Preparations. 

Glycerita (U. S. P.) or Glycerina (B. P.) are solutions of medicinal sub- 
stances in glycerin. 

Collodia, collodions, are solutions of medicinal substances in collodion. 
(See Part VI.) 

Aceta, or medicated vinegars, are solutions of medicinal substances in 
vinegar or acetic acid. 

Linimenta, liniments, embrocations, are preparations in which active rem- 
edies are dissolved or suspended in dilute alcohol, oils, or water. They gen- 
erally contain an oil or soap and are intended to be applied to the skin. 

d. Solid and Semi-Solid Preparations. 

Extracta, extracts, are formed from solutions such as tinctures, decoctions. 
or infusions by evaporation, which is continued until there remains a solid 
mass. The extracts thus contain all the substances which are taken up by 
the solvent, except those which are driven off or decomposed by the temper- 
ature at which evaporation is carried on. 

Pilulse, pills, are globular masses of small size, such as admits of their 
being easily swallowed. They are formed from extracts, or from powders, 
by the addition of some substance to give them the necessary cohesion and 
consistency. Pills generally weigh 0.1-0.3 G. (2-5 grs.). The U. S. P. de- 
termines the composition and size of the official pills, so that the dose can 
be modified only by ordering several pills to be taken at one time. The B. P. 
leaves the pills unformed, so that they may be prescribed of any size. The 
Pilulse of the B. P. really correspond not to the Pilulse, but to the Massse of 
the U. S. P. 

Massse (U. S. P.), masses, are preparations made up of the proper consist- 
ency for pills. They are invariably prescribed in the form of pills. 

Confectiones, confections or electuaries, are soft, solid preparations consist- 
ing of sugar or honey impregnated with some more active body. 

Suppositoria, or suppositories, are intended for insertion into the rectum, 
urethra, or vagina, and are, except in one or two cases, formed by mixing 
the active ingredient with cacao-butter. (See part VI.) Suppositories for 
the rectum are conical in shape and weigh about a gramme (15 grs.). Those 
for the urethra are of the same weight, but are pencil- shaped, while the 
vaginal suppositories are globular, and weigh about 3 grammes (45 grs.). 

Pulveres, powders, are simply dry substances in a state of fine division. 
Most of the official powders are mixtures of several active bodies. 

Triturationes (U. S. P.), triturations, are formed from powders by diluting 
them with nine parts of sugar of milk. 

Trochisci, troches, or lozenges, are solid masses, generally of a flattened 
shape, and consist of powders or other bodies, incorporated in sugar and gum. 
A very friable form of lozenge known as Tabellse, or tablet triturates (not 
official), is formed by pressing in moulds a mixture of powdered sugar and 
drugs, slightly moistened with alcohol. 

Lamellse (B. P.), or discs, are small discs formed of gelatin with some gly- 
cerin, each weighing 7 V~sV g r - They are impregnated with an active drug, 
and are applied to the conjunctiva in order to elicit the local effects. 

Unguenta, ointments, salves, are soft, oily substances which are applied to 
the skin by rubbing. (See page 49.) 

Oleata, solutions in oleic acid resembling the ointments in appearance and 
uses. 

Cerata (U. S. P.), cerates, resemble ointments, but are rendered harder by 
the addition of wax. (See page 50.) 



CLASSIFICATION OF DRUGS. 4i 

Emplastra, plasters, are adhesive bodies of a still harder consistency than 
cerates, and soften only when heated. (See Part VI.) 

Chartse, papers, are preparations of active substances which are spread in a 
thin layer upon paper, or are incorporated in it by dipping sheets of paper 
into a solution. 

Unofficial Preparations. 

Cachets, are thin discs of dough of the shape of a soup-plate and varying 
from £ in. to 1^ in. in diameter. When two of them are placed together 
with their concave sides toward each other, they form a receptacle in which 
powders are dispensed. The edges stick together when they are moistened. 
A somewhat similar method of dispensing is in gelatin capsules, which may 
be hard or soft, and which are made in different sizes. The hard capsule \s 
used for solids, the soft for liquids. Sometimes the latter contain as much 
as 15 c.c. (J fl. oz.), but these are difficult to swallow. 

Cataplasmata, or poultices, are not official preparations now, but are in 
common use. They are generally made of linseed meal, oatmeal, or bread 
crumb, which is formed into a paste with hot water, enclosed in thin cotton 
or linen and applied to the skin. Mustard and other remedies may be added 
to the poultice in order to induce special effects, and in some cases a poultice 
consists merely of drugs enclosed in a cloth sack, as in charcoal or spice 
poultices. 

Enemata, clysmata, or clysters, are liquid substances injected into the rec- 
tum for their local or general effects. (See page 31.) 

CLASSIFICATION OF DRUGS. 

Writers on pharmacology and therapeutics arrange drugs on many differ- 
ent principles. Thus a somewhat antiquated system classifies the vegetable 
remedies according to the botanical families from which they are obtained, 
but there is little advantage in this arrangement, for an order may include 
drugs which differ entirely in their action and in the therapeutic uses to 
which they are put, while, on the other hand, two widely separated botanical 
groups may contain identical poisons. Another classification of drugs is 
according to their therapeutic effects, and this might seem at first sight the 
most convenient for students of medicine. This plan has its drawbacks, 
however, for many drugs are used for a large number of different purposes. 
and it is impossible to describe them under each heading. In addition, the 
classification in groups is always liable to suggest a much closer resemblance 
in the effects of the individual drugs than really exists. Thus the drugs 
often classed as "cardiac stimulants" differ much, not only in their effects 
on the body in general, but in their action on the heart, and opinions may 
differ as to whether some of them stimulate or depress the heart. They 
certainly cannot be substituted for each other in the treatment of heart dis- 
ease, as is suggested by their being classified together under this heading. 
Finally, practical therapeutics can be taught only in the clinic, and in the 
teaching of pharmacology it seems advisable to direct the student's attention 
rather to the action of drugs than to the practical uses, which can be taught 
to much greater advantage in connection with the symptoms, prognosis, ami 
other clinical features of disease. The classification of drugs and poisons 
according to their action on living matter is the natural one, and is based 
on the same logical principle as the modern classification of plants in hot- 
any and of animals in zoology. The object is to group together those sub- 
stances which have most points of resemblance, whether they are obtained 
from the same or from different orders of plants, ami whatever relation 
they may bear to each other in therapeutics. This classification, which 
was introduced by Buchheim. has been further developed by Schmiedeberg 
an 1 his pupils. In the present state of knowledge it is necessarily imper- 



42 INTRODUCTION. 

feet, and many resemblances and affinities have not gained that recog- 
nition which they will doubtless receive in the future. Even in its pres- 
ent imperfect form, however, this classification is the most satisfactory 
one available, and, unlike the others, it can be easily subjected to such modi- 
fications as the advance of science renders necessary. If ever the ideal 
classification be attained, in which the grouping is based upon the chemical 
reactions of the poisons with the living protoplasm, this natural classification 
will be found to conform more easily to it than any based upon origin or 
temporary therapeutic uses. 

Resemblance in pharmacological action does not necessarily involve simi- 
larity in chemical composition, as has been already pointed out. But it is 
found that in many instances the members of a pharmacological group have 
some general chemical character which distinguishes them from others. 
Drugs which resemble each other in their pharmacological action, are often 
used for very different purposes in therapeutics, although this is much less 
frequently the case now than formerly. This is very generally due to the 
failure of the clinicians to observe the resemblance in the action of drugs. 
As they become more familiar with the results of animal experiment, they 
will recognize that in many instances drugs which they now regard as dis- 
tinct on account of superficial differences, really resemble each other in all 
important points, and may be substituted for each other in therapeutics In 
this way it is to be hoped that the natural classification of drugs will gradu- 
ally be found to approach more closely to the therapeutic. At the present 
time the continued use of the therapeutic classification can only tend to delay 
this consummation. 

In this volume, the classification adopted is that of Btichheim and 
Schmiedeberg, with some slight alterations which seemed to be de- 
manded by recent progress. The drugs are thrown into a large num- 
ber of groups which are named from the most prominent member, or 
from some marked property possessed by all. These groups are ar- 
ranged, as far as possible, according to their mutual resemblances. It 
has been found advisable to retain, for the most part, the divisions into 
organic and inorganic drugs, although this may, perhaps, have to be 
abandoned in the future. The first series of groups of the organic 
materia medica are possessed of the common property of inducing 
more marked local than general effects, and these may therefore be 
classified in one large subdivision. The second division of the organic 
drugs is formed of those whose pronounced general action obscures 
their local effects, when these are not entirely absent. The first few 
groups of this division are formed of those whose chief action is de- 
veloped on the central nervous system ; then follow those which in- 
volve more especially the peripheral nerves, muscles, and secretory or- 
gans ; these, again, pass into a series in which local irritant action is 
associated with powerful general effects, and through these into a se- 
ries of protoplasm poisons. The last series of organic groups consists 
of those acting chiefly on the heart and vessels directly. The groups 
of the inorganic drugs show less defined affinities, and are much more 
difficult to classify than the organic series. The salts of the alkalies 
and alkaline earths, the acids and alkalies may be thrown into a large and 
somewhat heterogeneous division, which is easily marked off from that 
of the heavy metals, which have many points in common in their ef- 



CLASSIFICATION OF DRUGS. 43 

fects in the organism, as in their chemical reactions. The latter divi- 
sion is led up to by phosphorus and arsenic, and several bodies which 
it is impossible to classify at present are placed between these and the 
first inorganic division. Another class is formed of a number of sub- 
stances which are either present in the normal body, or are merely sub- 
stitutes for normal secretions, and the final class is composed of a feu- 
preparations which are used only for their mechanical effects, and 
which for the most part are not drugs, although they are included in 
the pharmacopoeias. 

It must be emphasized that no attempt is made to draw hard and 
fast lines of demarcation between the different groups. The essential 
features of the natural system involve the recognition that this is im- 
possible. It has therefore been considered best not to indicate any 
definite point at which the discussion of poisons acting on the central 
nervous system ends and that of the drugs with peripheral effects be- 
gins. The student is always liable to lay more importance on such 
divisions than is intended by the writer, to list those on one side of 
the dividing line as central, those on the other as peripheral in action, 
whereas the transition is gradual. The six chief divisions are therefore 
the only ones indicated. 



PART I. 

ORGANIC SUBSTANCES WHICH ARE CHAR- 
ACTERIZED CHIEFLY BY THETR 
LOCAL ACTION. 

This class contains a very considerable part of the drugs included 
in the pharmacopoeias, although it bears a smaller proportion than for- 
merly to the other classes. There is still, however, in it a larger 
number of drugs which have practically identical effects, and there is 
no question that it might be considerably curtailed without loss to 
therapeutic practice. Many of its members are irritants, and these 
have been subdivided for convenience into groups according to the 
organs on which they exert their chief action and the purpose- for 
which they are used in therapeutics, as gastric, intestinal, cutaneous 
irritants. Others act as protectives, covering injured surfaces (demul- 
cents, emollients), and still others precipitate the proteids on the sur- 
faces to which they are applied (astringents). Others seem to act 
chiefly by affecting the taste, and finally a heterogeneous group which 
is used in the treatment of intestinal parasites, has been inserted here. 

I. DEMULCENTS. 

A large number of colloid substances — chiefly gums, dextrins, sugars 
and starches — owe their use in medicine, not to any changes they pro- 
duce in the cells with which they come in contact, but to the fact that 
they are cohesive and serve to protect surfaces mechanically. When 
they are applied to a sensitive surface, they retard the movement of 
fluid or air against it and thus preserve it from the effects of these 
agents. This may be illustrated by familiar examples in which the 
taste of food is altered by their presence, although they have often no 
taste or odor in themselves. Sugar dissolved in mucilage tastes less 
sweet than in water and acids are also less appreciated, as may be ob- 
served in many fruits. For example, the raspberry contains more acid 
and less sugar than the currant, but in the former the acid taste is con- 
cealed by the presence of large quantities of colloids, so that the rasp- 
berry is regarded as a sweet fruit, the currant as an acid one. Even 
cold is felt less when a colloid substance is present in the fluid swal- 
lowed ; thus, ice-cream or iced milk does not feel so cold on the tongue 
and throat as frozen water, because the colloid proteid substances form 
a protecting layer over the surface, and prevent the cold mass from 
reaching the sensory terminations so freely as it otherwise won hi. A 

45 



46 ORGANIC SUBSTANCES ACTING LOCALLY. 

number of experiments carried out by Tappeiner l show that other 
organs may be protected in the same way by colloid solutions. Strong 
salt solution applied to a motor nerve first stimulates and then slowly 
paralyzes it, but Tappeiner found that both of these effects are much 
less marked if the solution be made up with mucilage instead of with 
water, because the salt does not reach the nerve so readily. In the 
same way, intense pain is caused in a wound by strong salt solution, 
but is much less severe if the solution contain colloid material. 

When demulcents reach the stomach, they appear to coat the wall 
and thus to alter the sensation arising from food, for Quincke found in 
a case of gastric fistula that the patient could distinguish milk from 
water even when it was passed directly into the stomach, and Pawlow 
states that the presence of starch in the stomach alters the secretion 
induced by food. Tappeiner found that much less inflammation of the 
intestine is caused by irritants if they are suspended in demulcents than 
if they are dissolved in water, and this accords with the observation 
that beer, which contains large quantities of dextrin, is less irritant to 
the stomach than a solution of alcohol of equal strength. The digestion 
of proteids outside the body is retarded by the presence of the demul- 
cents, and probably this is also true of the process in the stomach. 
Colloid bodies also retard the absorption of fluids from the stomach and 
bowel, and this leads to a feeling of distention, which is much less 
marked if the same amount of fluid be swallowed without colloid ; for 
instance, water is absorbed more rapidly than milk or beer. 

The slow absorption of colloid fluids allows time for decomposition, 
and this may give rise to irritation and catarrh. The colloids them- 
selves are absorbed very slowly, and probably only in a condition of 
semi-decomposition. After absorption, they are oxidized in the tissues 
and therefore act as foods to some extent, although their slow absorp- 
tion prevents their being of much value. They have, of course, no 
effect as demulcents after absorption, but the large quantity of fluid 
with which they are generally taken may be of benefit in some condi- 
tions. 

Demulcents are used to cover inflamed surfaces ; in tonsillitis, for 
example, they may be applied as gargles, or better by sucking lozenges 
containing them. They are not often applied externally for this pur- 
pose, as they are liable to serve as media for the growth of micro- 
organisms. In gastric and intestinal catarrh their use is objectionable 
for the same reason, their slow absorption leading to decomposition 
with the formation of irritants, which may do more harm than is coun- 
terbalanced by their protective action. 

In acute irritant poisoning the demulcents are often of great value as 
they protect the stomach wall from the effects of the poison. The best 
remedy in these cases, because the most readily obtainable, is milk or 
white of eggs. 

Their effects in retarding the absorption of other remedies may be 
taken advantage of. Thus when the effect of alcohol on the stomach 
1 Tappeiner, Miinchen. med. Woch., 1899, No. 38. 



DEMULCENTS. 47 

or bowel is desired, it is given as wine, which contains colloid material 
and is therefore, absorbed slowly ; it must be noted, however, that 
these same colloids delay digestion much more than alcohol itself. In 
the same way opium and extract of nux vomica are prescribed when 
the local action on the bowel and stomach is desired, while the pure 
alkaloids, morphine and strychnine, are administered for their effects 
after absorption. 

Demulcents are often given instead of pure water in cases where it 
is desired to administer large quantities of fluid, as they have more 
" body " and are more agreeable to the taste. Thus, badey water or 
some other demulcent may be advised in order to dilute the urine when 
it is too concentrated or too acid. The thirst of fever is often assuaged 
much better by these than by water alone. 

Demulcents are often used as the basis of enemata which are intended 
to be absorbed, because solutions containing colloids are less irritant 
and therefore less liable to set up peristalsis than pure water. For 
this purpose starch solution is generally used. 

Pbeparations. 

Acacia (U. S. P.), Acaciae Gummi (B. P.) (gum arabic), a gummy exuda- 
tion obtained from Acacia Senegal, consists of the potassium, magnesium, 
and calcium salts of a weakly acid substance, arabin or arabinic acid 
(C 6 H 10 O 5 ). It is soluble in equal parts of water, and is used as a demulcent, 
but more largely to give cohesion to pills, lozenges, etc., and to suspend 
powders or oils in water, in emulsions and mixtures. 

Mucilago Acacia (U. S. P., B. P.). — About 1 part acacia in 2 of water. 

Syrupus Acacise (U. S. P.). 

Tragacantha (U. S. P., B. P.), a gummy exudation from various species 
of Astragalus, contains arabin and tragacanthin in combination with potas- 
sium, magnesium, and calcium. Tragacanthin differs from arabin in not 
dissolving, but merely swelling up into a jelly in water. Tragacanth is used 
chiefly to suspend heavy powders in water. 

Mucilago Tragacantha (U. S. P., B. P.), formed of tragacauth. 
glycerin and water. In the B. P. alcohol is used instead of glycerin. 

Glycerinum Tragacanthse (B. P.), a solution of tragacanth in glycerin and 
water. 

Pulvis Tragacanthse Compositus (B. P.), contains tragacanth, gum acacia, 
starch and sugar. Dose, 20-60 grs. 

Sassafras Medulla (U. S. P.), the pith of Sassafras variifolium (sassafras). 

Ulmus (U. S. P.), the inner bark of Ulmus fulva (slippery elm). 

Althaea (U. S. P.), the root of Althaea officinalis (marsh-mallow). 

Linum (U. S. P., B. P.), the seed of Linum usitatissimum (linseed). 

Linum Contusum (B. P.), crushed linseed. 

Mucilago Sassafras Medullx (U. S. P.). 

Mucilago Ulmi (U. S. P.). 

Syrupus Althsese (U. S. P.). 

These all contain colloid substances which are extracted with hot water, 
and which are believed to be nearly related to arabin, although their com- 
position is not accurately known. They are largely used in domestic medi- 
cine as demulcents in sore throat, and may be prescribed to suspend powders 
or oils. The syrup of marsh-mallow is a pleasant flavor. 

Triticum (U. S. P.), the rhizome of Agropyrum repens, or couch-grass, 
contains mannite, laevulose, and a starchy substance, triticin. Its decoction 
is used as a beverage in fever, and to dilute the urine. It has a certain 



48 ORGANIC SUBSTANCES ACTING LOCALLY. 

popular reputation as a diuretic in suppression of the urine, calculus, etc., 
but this is entirely unmerited, for it increases the urine simply by the water 
given with it. 

Amylum (U. S. P., B. P.), or starch, may be formed into a jelly by boiling 
in water, and may then be used for the same purpose as the demulcents. 

Glyceritum Amyli (U. S. P.), Glycerinum Amyli (B. P.), is a jelly formed 
by heating starch with water and glycerin. Starch in various forms— arrow- 
root, sago, tapioca, etc. — is an important element in the diet of the sick, but 
this subject can not be entered on here. 

Amygdala Dulcis (U. S. P., B. P.), or sweet almonds, the seed of Prunus 
amygdala dulcis, contains a fixed oil and emulsin, a ferment, but, unlike the 
bitter almond, no amygdalin. When triturated with water it forms an 
emulsion, or mixture, which is bland and demulcent. 

Emulsum Amygdalae (U. S. P.), Mutura Amygdalae (B. P.). 

Pulvis Amygdalae Compositus (B. P.) contains sugar and acacia with almond. 

Syrupus Amygdalae, (U. S. P.) is formed from a mixture of sweet and bitter 
almonds, and therefore contains a small proportion of prussic acid, but may 
be used in the same way as the demulcents with per feet safety. 

Glycyrrhiza (U. S. P.), Glycyrrhizae Radix (B. P.), or liquorice-root, 
the root of Glycyrrhiza glabra (var. glandulifera), is used as a demulcent, 
and more largely to flavor medicines. It has a pleasant, sweet taste, owing 
to the presence of Glycyrrhizin, an acid glucoside, which is combined with 
calcium and ammonia in the plant, and is not soluble in cold water, but swells 
up in it to a jelly-like mass. Glycyrrhizin is probably decomposed in the 
body ; the urine is often found to contain a reducing body after the admin- 
istration of liquorice. 

Extra ctum Glycyrrhiza (U. S. P., B. P.). 

Extractum Glycyrrhizae Purum (U. S. P.). 

Extractum Glycyrrhizae Fluidum (U. S. P.), Extractum Glycyrrhizae Liquidum 
(B. P.). 

Glycyrrhizinum Ammoniatum (U. S. P.), the ammonium salt of glycyrrhizin. 

Pulvis Glycyrrhiza Compositus (U. S. P., B. P.) contains senna. 
Dose, 2-8 G. (30-120 grs.). 

Trochisci Glycyrrhiza et Opii (U. S. P.). 

Mistura Glycyrrhiza Composita (U. S. P.), " Brown Mixture," con- 
tains opium, antimony and spirits of nitrous ether. Dose, 15-30 c.c. (1-2 
tablespoonfuls). 

The extract is largely used in the form of lozenges for its demulcent ac- 
tion, and is very frequently used to make up pills. It is slightly laxative, 
and may be used as a pleasant aperient for children ; the compound powder 
is more reliable for this purpose owing to its containing senna, one of the 
vegetable purgatives. 

The lozenges and the brown mixture contain opium and are used largely 
in cough and in catarrh of the air passages. 

Numbers of other substances are used as demulc nts in domestic medi- 
cine, and are found in different pharmacopoeias. Examples of these are 
barley (Hordeum), salep, verbascum and quince seeds. 

Cetraria (U. S. P.), Iceland moss, is a lichen (Cetraria islandica), and 
contains two nearly allied starch bodies (lichenin and isolichenin) together 
with acids, of which cetraric acid is the most important, as it gives the decoc- 
tion a bitter taste. The acids can be removed by soaking in dilute alkaline 
solutions for some time. 

Chondrus (U. S. P.) (Irish moss or Carragheen), Chondrus crispus and 
Gigartina mamillosa, both seaweeds gathered on the coasts of Ireland and 
Massachusetts. Chondrus contains a carbohydrate, carrageenin. The de- 
coction forms a jelly when cold, and was formerly supposed to form a valu- 
able food in illness, but it is of little value for this purpose, for only about 
■h~h of the jelly is solid matter, the rest water. 



EMOLLIENTS. 49 

Decoctum Cetrarise (U. S. P.). 

Vitellus (U. S. P.) and Glyceritum Vitelli (U. S. P.), a mixture of yolk of 
egg and glycerin, may also be used as demulcents or to suspend insoluble 
drugs. 

Inula (IT. S. P.) (elecampane), the root of Inula Helenium, contains a 
starchy body, inulin, along with a volatile oil and camphor. 

II. EMOLLIENTS. 

Emollients are bland, oily substances which are applied to the 
skin to protect it from irritation, and to render it softer and more 
elastic, and thus bear the same relation to the skin as the demulcents 
to the mucous membranes. Their effect in rendering the skin softer 
and more pliable may be due in part to their penetration into the 
surface layers, but may also be explained by the slight congestion 
induced by the rubbing and massage used in their application. 

The older emollients were chiefly animal and vegetable fats and 
oils, but several newer drugs of this class are derived from petroleum. 
The effects of these drugs when applied to the skin are purely local. 
No doubt some small percentage is absorbed into the tissues, but this 
has no known effect in man, and although the fats and oils are valu- 
able foods when taken internally, this plays no part in their effects 
when applied to the skin. It has been proposed, it is true, to admin- 
ister oils by the skin in cases of inanition in which they are not borne 
by the stomach and intestine, but no very satisfactory results have 
been recorded from this very laborious method of treatment. 

The emollient preparations promote the absorption of drugs dis- 
solved in them, because they mix readily with the thin layer of oily 
sebaceous matter which covers the epithelium. The active substances 
dissolved in them therefore come into intimate contact with the absorb- 
ing cells lining the ducts of the glands, while watery solutions are 
separated from the lining cells by a layer of sebum. If this layer be 
dissolved off by alcohol, watery solutions are also absorbed rapidly, 
and alcoholic solutions are absorbed as quickly as oily solutions, be- 
cause the alcohol is miscible with the sebum. On the other hand 
solutions in water come into more intimate contact with the cells of the 
mucous membranes and with the subcutaneous tissues, and are there- 
fore more readily absorbed by these than oily solutions. To ensure 
rapid absorption, a drug should be dissolved in some emollient if it is 
to be absorbed by the skin, in water when it is to be administered 
internally or hypodermically. Solutions in oil of such antiseptics as 
carbolic acid are much less powerful than those in water, because car- 
bolic acid being more soluble in oil fails to diffuse into the watery proto- 
plasm of the microbe, for which it has less affinity. (Sec Antiseptics 
of the Benzol Series.) But antiseptics which are more soluble in water 
than in oils are said to be equally active in both solvents. 

The emollients are applied as protectives in abrasions, outs, bruises, 
chapped hands, burns ; they are less often used alone in extensive skin 
diseases, but are usually prescribed in these as the basis of ointments 
4 



50 ORGANIC SUBSTANCES ACTING LOCALLY. 

in which other remedies are incorporated. There is no question that 
the protection afforded to the part and the exclusion of the air by 
the oily emollient plays an important part in the action of these reme- 
dies, and it seems probable that in many cases equally good results 
would follow the application of the emollient without any active 
ingredient. 

Preparations. 

Adeps (IT. S. P., B. P.), lard ; the prepared internal fat of the abdomen 
of the pig, purified by washing in water, melting and straining. 

Adeps Benzoinatus (U. S. P.), Adeps Benzoatus (B. P.), benzoinated lard, is 
prepared from lard by the addition of benzoin, which is slightly antiseptic 
and preserves it from becoming rancid. 

Unguentum (U. S. P.), ointment, is a mixture of lard and yellow wax. 
It was formerly known as Unguentum Simplex, and is the basis of many 
other ointments. 

Unguentum Diachylon (U. S. P.) is formed from lead plaster and olive oil, 
perfumed with oil of lavender. The lead is inert, the action being identical 
with that of ordinary ointment. 

Unguentum Aqu.e Ros^: (U. S. P., B. P.), cold cream, is formed of sper- 
maceti, white wax, oil of almonds, and some borax, scented with rose water. 

Sevum (U. S. P.), Sevum Prseparatum (B. P.), mutton suet, is obtained 
from the abdominal fat of the sheep. 

Lard and suet have the ordinary constituents of animal fats, stearin, pal- 
mitin and olein. They are seldom used alone, but form the basis of numer- 
ous ointments. These animal fats tend to putrefy, and are then rendered 
irritant by the presence of free acids (rancidity), and have therefore been 
replaced to a considerable extent of late years by other preparations which 
do not suffer from this drawback. 

Adeps Lanae Hydrosus (U. S. P., B. P.), hydrous wool-fat, lanolin, the 
purified fat of sheep-wool, mixed with not more than 30 per cent, of water. 

Adeps Lanse (B. P.), wool-fat without water. 

Lanolin has been used extensively in medicine only in the last few years. 
It consists of cholesterin esters with some impurities, does not become ran- 
cid, and differs from the older fats also in being miscible in twice its weight 
of water without losing its ointment consistency. Lanolin is very often used 
as an emollient application, as well as to form a basis for more active drugs. 

Other preparations of wool-fats are known as lanichol and alapurin. 

Petrolates or Paraffins. When the more volatile constituents of petroleum 
are distilled off, there remain a number of higher hydrocarbons, chiefly of 
the marsh gas series, which are used in medicine as emollients. The lower 
of these hydrocarbons are fluid at ordinary temperatures and are known as 

Petrolatum Liquidum (U. S. P.), Paraffinum Liquidum (B. P.), a colorless, 
oily transparent liquid without odor or taste. When these are removed 
there remains 

Petrolatum molle (U. S. P.), Paraffinum molle (B. P.), soft petro- 
late, vaselin, which has the consistency of an ointment, is yellow or white 
in color, and is liquefied a few degrees above the temperature of the blood. 
When the distillation is carried further, the residue is solid at ordinary tem- 
peratures, and is known as 

Petrolatum Spissum (U. S. P.), Paraffinum Durum (B. P.), or hard paraffin, 
which melts at a somewhat higher temperature than vaselin. 

Unguentum Paraffini (B. P.) is a mixture of three parts of hard paraffin 
with seven parts of vaselin. 

By mixing the petrolates a salve of any desired consistency may be ob- 
tained. Soft petrolate is often known as petrolatum, as it is much more 
extensively used than the others. It is used as an emollient, and as a basis 
for ointments and has the advantage over the older lard and suet that it 






EMOLLIENTS. 5 1 

does not become rancid. Liquid vaselin has been used to dissolve irritant 
substances for subcutaneous injection, as much less pain is caused when they 
are dissolved in vaselin than when water is used. Sobieranski l has shown 
that vaselin rubbed into the skin is absorbed to some extent, and may be 
recovered from the muscles and to a less extent from other organs. Babbits 
lost flesh and some of them died under the continued application of vaselin, 
but this may have been due to the manipulation and not to the drug itself. 

Several Oils are also used as emollients. 

Oleum Olivse (U. S. P., B. P.), olive oil, a fixed oil obtained from the ripe 
fruit of the olive, Olea europaea. 

Oleum Lini (U. S. P., B. P.), Linseed or Flaxseed oil. 

Oleum Amygdalae Expressum (U. S. P.), Oleum Amygdalse (B. P.), a fixed 
oil expressed from bitter or sweet almonds. It is to be distinguished from 
the volatile oil obtained from the bitter almonds. The fixed oil contains no 
prussic acid. 

Oleum Sesami (U. S. P.), Sesame oil, Teel oil, Benne oil. 

Oleum Gossypii Seminis (U. S. P.), Cotton-seed oil. 

Oleum Adipis (U. S. P.), oil of lard. 

These all resemble each other in their composition, and may be used as 
emollients. Olive oil is generally preferred to the others, but is much more 
expensive, and it is probable that much of the so-called olive oil is really 
purified cotton-seed oil. Olive oil has been advised as a cholagogue, but has 
been shown by more exact methods of research to have no effect whatever 
on the secretion of the bile. It sometimes gives relief in biliary colic how- 
ever, an effect which may perhaps be due to its acting as a demulcent in the 
duodenum, and thus lessening the irritation of the gall duct. It is admin- 
istered in large doses for this purpose — 100-150 c.c. (3-5 fl. oz.) in 24 hours. 

Cera Flava (U. S. P., B. P.), yellow wax. 

Cera Alba (U. S. P., B. P.), white wax prepared from the yellow by 
bleaching. 

Cetaceum (U. S. P., B. P.), spermaceti, obtained from the cachelot (Phys- 
eter macrocephalus), one of the whales. 

These three preparations are not used alone, but are often added to the 
emollients and ointments in order to give them a firmer consistency, which 
is especially desirable in hot climates and in summer. 

Ceratum (U. S. P.) a mixture of 3 parts of wax with 7 of lard. 

Ceratum Cetacei (U. S. P.), Unguentum Cetacei (B. P.), is a mixture of white 
wax and spermaceti and olive or almond oil. 

Glycerinum (U. S. P., B. P.), Glycerin, a liquid obtained by the decom- 
position of animal or vegetable fats or fixed oils, and containing not less than 
95 per cent, of absolute glycerin, C 3 H 5 (OH) 3 ; clear, colorless, of a syrupy 
consistence, oily to the touch, with a sweet taste and no odor, soluble in 
water and alcohol. 

Glyceritum Amyli (U. S. P.), Glycerinum Amyli (B. P.), glycerite of starch. 

Glyceritum Vitelli (U. S. P.), glyconin, glycerite of yolk of eggs, may be 
used as a protective, but is more largely prescribed to form emulsions. 

Glycerin is used as a solvent for a number of other drugs, the prepara- 
tions being known as glycerites (U. S. P.), glycerines (B. P.). 

Glycerin is somewhat irritant to the unbroken skin? when it is ap- 
plied in the pure form, and even diluted glycerin causes pain and 
smarting when it is applied to unprotected surfaces such as cats or 
burns, but the pain soon disappears, and glycerin then acts as a pro- 
tective. The irritation is due to the glycerin abstracting the fluids of 
the tissues owing to its avidity for water. Glycerin and its prepara- 
tions are used very extensively as applications to slight wounds, in ir- 

iArch. f. exp. Path. u. Pharm., xxxi.. p. 329. 



52 ORGANIC SUBSTANCES ACTING LOCALLY. 

ritation of the skin and lips from exposure to cold, and in similar con- 
ditions. They are often applied to hard, dry crusts on the skin in 
order to soften them and permit of their removal. 

The irritant action of glycerin causes peristalsis and evacuation of 
the bowels when small quantities are injected into the rectum. The 
glycerin is said to pass upwards from the anus to the sigmoid flexure 
or even further, and to increase the peristalsis of the greater part of 
the large intestine from its contact with the epithelial walls. It is 
very probable, however, that the local irritation of the lower part of 
the rectum is sufficient to set up reflex movement of the bowel. Small 
quantities of glycerin injected into the rectum do not cause diarrhoea ; 
the stool is of almost ordinary consistency, and no pain or colic is felt 
subsequently, nor does the remedy cause more than one evacuation. 
Glycerin may be injected into the rectum for this purpose (dose 2-5 c.c, 
J— 1 teaspoonful), but a more convenient form is the glycerin supposi- 
tories, Suppositoria Glycerini, which are made up with stearic acid 
and sodium carbonate, U. S. P., with gelatin, B. P. These suppositories 
are found not to keep well, as the glycerin tends to attract moisture 
and then escapes ; to avoid this they are often encased in paraffin, which 
is broken off immediately before they are inserted. Glycerin sup- 
positories are used in constipation instead of the ordinary aperients, 
and they have also been advised in parturition to increase the pains. 
Large doses of glycerin taken internally sometimes cause purgation, 
but it is not a reliable remedy when administered in this way. 

Glycerin in large quantities is poisonous whether it is taken by the mouth 
or injected hypodermically or intravenously. It is true that no case of 
glycerin poisoning in man is known, but large doses are fatal to animals in 
the course of a few hours. The chief symptoms are restlessness, agitation, 
acceleration of the heart and respiration, general weakness, tremor and 
convulsions, which finally end in somnolence, coma, and death from failure 
of the respiration. The convulsions are marked only after large doses, 
when they may assume a tetanic character. A rise in the temperature has 
been noted by several observers, followed by a fall which continues until 
death. When glycerin is injected subcutaneously in large quantities, 
haemoglobin appears in the urine, while this is rarer when it is given by the 
mouth, and scarcely ever appears after intravenous injection. This is ob- 
viously due to the destruction of the red blood cells, but glycerin added to 
the drawn blood does not act so strongly on it as many other bodies which 
cause no hemoglobinuria. Filehne explains the appearance of haemoglobin 
in the urine after the subcutaneous injection of glycerin by supposing that 
the glycerin remains outside the vessels for some time, and withdraws the 
fluid from the red cells as they pass through the poisoned zone. As the cells 
return into the larger vessels, they take up fluid again and give off 
haemoglobin. On the other hand, when glycerin is injected into the blood, 
it diffuses rapidly all over the body, and the blood cells are less acted on by 
the diluted poison and do not alternately shrink and swell in size. He 
supports his explanation by an ingenious experiment, in which the blood 
cells were first shrunk by glycerin and then allowed to return to the circu- 
lation ; in this way he was able to induce haemoglobinuria by the intravenous 
injection of glycerin. In addition to its action on the blood cells, glycerin 
apparently acts directly on the central nervous system, as is shown by the 
violent convulsions. Glomerulonephritis has also been observed in animals. 



EMOLLIENTS. 53 

Glycerin is absorbed rapidly from the intestine, and undergoes combustion 
in the tissues, only a very small fraction of it reappearing in the uriue. 
Some authors describe a reducing substance in the urine after the ingestion 
of glycerin, but this has not been confirmed on more careful investigation. 

It follows from the fact that glycerin is oxidized in the tissues that it must 
supply the body with energy and act in some sense as a food. This is of 
interest chiefly because, the ordinary fats being compounds of glycerin, a 
certain amount must be contained in the food, but it is also of some thera- 
peutic importance, because glycerin has been advised as a food in inanition, 
and has even been said to rival cod-liver oil. In respect to its value as a 
food, glycerin resembles ordinary alcohol, being readily absorbed, and un- 
doubtedly increasing the total energy of the body. But it is still undecided 
how far it leads to an economy of the nitrogenous tissues, as the fats and 
carbohydrates do. Its combustion saves a certain amount of the fat of the 
body from being destroyed, but glycerin tends to increase the non-nitrogen- 
ous, and not the nitrogenous reserve of the body, and is therefore of only 
secondary importance as a food, although, like alcohol, it may be of value 
under certain conditions. 

Glycerin has been said to have some effect on the sugar formation in the 
tissues. In some forms of experimental glycosuria, apparently less sugar is 
found in the urine if glycerin be administered, and in a certain number of 
cases of diabetes in the human subject, some improvement is said to have 
occurred under glycerin treatment. No satisfactory explanation of this 
point has been offered. Quite apart from its supposed action on diabetes, 
glycerin has been used as a substitute for sugar in this disease, but its place 
has been taken of late years by saccharin. 

Glycerin has been shown to possess some virtue as an antiseptic, probably 
from its withdrawing water from the microbes, but like the oils (page 48) it 
is a less suitable solvent for many antiseptics than water. 

Bibliography of Glycerin. 

Dujardin-Beaumetz and Audige. Bull, de Therap., xci., p. 51. 

Plosz. Pfl tiger's Arch., xvi., p. 153. 

Ransom. Journ. of Phys., viii., p. 99. 

Schwahn. Eckhard's Beitrage zur Anatomie und Physiol og., viii., p. 167. 

Filehne. Virchow's Arch., cxvii., p. 413. 

Munk. Virchow's Arch., lxxvi., p. 119 ; Pfl tiger's Arch., xlvi., p. 303. 

Arnschink. Zeitschr. f. Biol., xxiii., p. 413. 

Christomanos. Virchow's Arch., clvi., p. 582. 

Wunschheim. Arch. f. Hygiene, xxxix, p. 101. 

Along with the emollients, or oily protectives, may be mentioned 
another class of mechanical agents, the Dusting Powders. Any dry, 
insoluble, fine powder applied to irritated surfaces of the skin, or 
slight abrasions, will protect these from the air, and from contact with 
the clothes and other sources of pressure. These powders, at the same 
time, soak up any secretions, and render the injured spot less liable to 
bacterial infection, as they form a more or less impermeable crust. 
Powders used for this purpose should not be absorbed, or, if absorb- 
able, should not induce any toxic effects. Those most commonly em- 
ployed are the phosphate and carbonate of lime, talc (magnesium 
silicate), fuller's earth and kaolin (aluminum silicates), starch, and 
lycopodium (U. S. P.), which consists of the spores of Lycopodium 
clavatum (club moss). 




54 ORGANIC SUBSTANCES ACTING LOCALLY. 

A large number of powders are used as surgical dressings, most of 
them being credited with more or less antiseptic power. In many in- 
stances, however, their antiseptic action is so slight that it would ap- 
pear that most of their virtues are due to their mechanical properties, 
and not to their bactericidal action. 



III. SUGARS AND FLAVORING SUBSTANCES. 

Sugars are used in medicine chiefly to disguise preparations of un- 
pleasant taste, and in the small quantities usually employed have little 
further effect. In large quantities sugars, like other diffusible bodies, 
act as irritants to the stomach and bowel, and comparatively small 
quantities of some sugar substances possess an aperient action. Thus 
molasses and imperfectly refined sugar have some reputation in do- 
mestic medicine as aperients, and honey, manna, Cassia fistula, and 
several fruits are included as mild laxatives in the pharmacopoeias. 
They are scarcely prescribed alone in medicine, but are used to give 
bulk to preparations of the stronger purgatives, such as senna. Their 
aperient action seems to be due to their colloid form, as pure sugar has 
no such effect, and it is possible that they merely delay the absorption 
of fluid, and thus cause softer evacuations than would otherwise occur. 

Preparations. 

Saccharum (TJ. S. P.), Saccharum Purificatum (B. P.), cane sugar. 

Syrupus (U. S. P., B. P.), a concentrated solution of sugar. Syrup is the 
basis of a large number of medicated syrups of the pharmacopoeias. Sugar 
and syrup are used exclusively to sweeten mixtures and to aid in the suspen- 
sion of insoluble bodies. In place of ordinary syrup many of the flavored prep- 
arations may be used, such as syrup of citric acid, of acacia, of almonds, etc. 

Saccharum Lactis (U. S. P., B. P.), sugar of milk, lactose, is not so sweet 
as ordinary sugar, and is much less liable to deliquesce, so that it is used 
largely to give bulk to powders. It has been said to have diuretic properties 
when given with large quantities of water, and to cause purgation when 
given in a more concentrated solution. Asses' milk contains more lactose 
than cows' milk, and has been recommended for its slight aperient action in 
chronic constipation. 

Mel, honey, and Mel Despumatum (TJ. S. P.), Mel Depuratum (B. P.), or 
clarified honey, are used to give taste to mixtures, and have a very slight 
aperient action, so that they may be advised as articles of diet in habitual 
constipation. Some medicated honeys are used, of which Mel Rosse is in- 
cluded in the U. S. P., Mel Boracis in the B. P. 

Oxymel (B. P.) is a mixture of honey and acetic acid. Dose, 1-2 fl. drs. 

Syrupus Glucosi (B. P.), a mixture of liquid glucose and syrup. 

Rubus Idaeus (TJ. S. P.), Raspberry fruit, is used to form the Syrupus Rubi 
Idsei (U. S. P.), which is used as a flavoring agent. Raspberry contains 
only a small quantity of sugar in proportion to its acid, but the taste of the 
latter is concealed by the presence of large quantities of colloid. 

Manna (TJ. S. P.), a saccharine exudation of Fraxinus ornus (Flowering 
Ash), contains about 50-75 per cent, of mannite, C 6 H 8 (OH) 6 , a hexatomic 
alcohol of sweetish, sugary taste. It has slight aperient properties when 
taken in large quantities. 

Cassia Fistula (TJ. S. P.), purging Cassia, the fruit of Cassia fistula. 

The pulp, Cassias Pulpa (B. P.), contains considerable quantities of sugar. 



SUGAES AXB FLA VOEIXG SUBSTAXCES. 55 

Tamarindus (U. S. P., B. P.), tamarinds ; Ficus (U. S. P., B. P.), figs ; 
Prunum (U. S. P., B. P.), prunes, all contain sugar in considerable quantity! 

These are used as mild aperients and flavoring agents, generally in combi- 
nation with more powerful remedies. Thus manna is used in Infusum 
Sennse Co. (U. S. P.), and the others form ingredients of Confectio 
Sennse. They are not prescribed alone, but the fruits may be advised as 
articles of diet where a mild laxative is required. The tamarind pulp may 
owe its aperient action in part to the presence of tartrates, citrates, malates 
and other cathartic salts. (See Saline Cathartics.) 

Frequently other flavors are preferred to sugar, which is especially 
disliked in fever cases, as sweet fluids do not quench the thirst so effect- 
ually as acids and bitters. Many of the preparations of the volatile 
oils and some of the demulcents are used almost exclusively as flavor- 
ing agents, and in some both sugar and volatile oil are combined, as in 
the syrups. 

Instead of sugar some artificial compounds have been introduced of 

CO 
late years. Glusidum (B. P.) or Saccharin, C 6 H 4 <<^ >NH, and its 

SO ^TT 

sodium salt, C 6 H 4 <p,A^ 2 or soluble saccharin, are the best known 

of these. Saccharin is a light, white, crystalline powder, soluble in 
400 parts of water and in 25 parts of alcohol. It is about 500 times 
as sweet as sugar, and gives a distinct flavor to 70,000 times its 
weight of water. Dulcin, another a romatic compound, is said to be 
even sweeter than saccharin. None of these taste exactly like sugar, 
however, there being a distinct flavor besides that of sweetness, and 
patients generally object to them after a short time. They have been 
used as substitutes for sugar in diabetes, a disease in which sugar is to 
be avoided as far as possible. Artificial digestion with saliva, gastric 
juice, or diastase is said to be hindered somewhat by saccharin, 1 while 
the soluble saccharin delays the proteolysis of the gastric juice only ; 
and it is said that the prolonged use of these bodies often leads to di- 
gestive disorders. 2 Like the other derivatives of benzol saccharin has 
some antiseptic action and tends to lessen the putrefaction of the in- 
testinal contents. Even very large doses of saccharin may be injected 
intravenously in animals without other effect than some depression and 
stupor. 

Some pharmacopceial preparations are designed to give color to solutions, 
but are seldom or never prescribed, although they are sometimes added l>y 
the pharmacist. 

Coccus (U. S. P., B. P.), cochineal, the dried female of Coccus Cacti. 

Tinctura Cocci (B. P.). 

Crocus (U. S. P., B. P.), saffron. 

Tincturi Croci (U. S. P., B. P.). 

Santalum Rubrum (XL S. P.), Pterocarpi Lignum (B. P.). red Banders, 
saunders or sandal wood. 

Rhceados Petala (B. P.), the fresh petals of Papaver Rhceas, red poppy. 

Syrupus Ehceados (B. P.), h-1 fl. dr. 

Poppy petals contain none of the alkaloids of opium. 

1 Eiegler, Arch. f. exp. Path. u. Pharm., xxxv., p. 306. 
2 Bornstein, Zeitschr. f. klin. Med., xl., p. 



56 ORGANIC SUBSTANCES ACTING LOCALLY. 

IV. SIMPLE BITTERS. 

This group includes a number of substances which have little in 
common except their bitter taste and their comparative inactivity in 
the body. Several alkaloids may be placed in it, Berberme, Buxine, 
Menispermine and Canadine, for, although these are poisonous in very 
large quantities, they are harmless in those in which tiiey are contained 
in the preparations used in therapeutics. In addition to these there 
may be placed in it numerous neutral bodies, possessing an intensely 
bitter taste, but with little or no further action, such as the Quassiins, 
Columbia, and a few weak acids and glucosides. 

Pharmacological Action. — These substances, or rather the prepara- 
tions containing them, are largely used in therapeutics in order to in- 
crease the appetite, and their administration is often followed by a dis- 
tinct improvement in the digestion and an increase in weight. 

Alimentary Tract. — The explanation of these effects is still obscure, 
although a large number of investigations have been made as to their 
effects in the stomach. In experiments with artificial digestion the 
pure principles have generally been found without influence on the ac- 
tivity of both gastric and pancreatic fluids, the slight variations ob- 
served lying within the limits of error ; and where any distinct effect 
has been observed, it has generally been a retardation of the process. 
The ordinary therapeutic preparations, on the other hand, generally 
delay artificial digestion, owing to the presence of tannic acid and colloid 
substances. The bitters neither destroy nor greatly retard the growth 
of bacteria in culture media, and most of them seem to be without ef- 
fect on the yeast fermentation of sugar solutions, although Vas found 
that quassiin retarded it somewhat. The absorption from the stomach 
is unchanged by the presence of bitters. 

In regard to the effect of the bitters on the secretion of the stomach, 
Reichrnann states that in man the bitters taken during gastric digestion 
do not affect the secretion, although they seem to retard the proteolysis. 
When bitters are taken on an empty stomach, less gastric juice is 
secreted immediately than if the same amount of water had been swal- 
lowed, but some time afterwards a very active secretion occurs. Reich- 
mann, therefore, advises the bitters in cases of insufficient acidity of the 
gastric juice, the remedy to be taken half an hour before meals. On 
the other hand, in hyperacidity the bitters may aggravate the condi- 
tion. This statement is in accordance with the observations of Bokai, 
that the secretory cells of the peptic glands present the histological 
appearances of activity after the bitters have been ingested. 

In animal experiments, the movements of the stomach are said to 
be somewhat augmented by the hitters, and poisonous doses of several 
of them increase the movements of both stomach and bowel, and cause 
considerable hyperemia. But it is unknown whether this action is 
common to all the bitters, and whether the small quantities used in ther- 
apeutics cause any increase in the blood supply. According to Reich- 
mann, the movements are probably somewhat less than usual in man 






SIMPLE BITTERS. 57 

Pohl found that bitters given by the stomach increase to a marked 
extent the leucocytes in the blood of the dog, and this may possibly aid 
in the absorption of the food. Eamm has shown that this holds true 
for man, and adds that the red blood cells are also augmented. The 
secretions of the pancreas and the bile are unaffected by the bitters. 
In the mouth the bitters cause a reflex flow of saliva, and it has been 
suggested that this may in part explain their therapeutic effect. Large 
quantities are said to cause a burning sensation in the oesophagus and 
stomach. 

The whole literature on the action of the bitters is full of contradic- 
tions, which is perhaps to be explained by the fact that comparative] v 
few investigators have examined their effect in human digestion, and 
many have contented themselves with the results of intravenous injec- 
tion in animals. The most probable explanation is that of Reich man n, 
that the gastric secretion is increased. It may be suggested here that 
this does not involve a direct action on the secretory epithelium, for 
Pawlow and his pupils have shown that the chief factor that deter- 
mines the activity of the gastric secretory cells is the odor and taste of 
the food. In dogs with gastric fistulse, in which the food swallowed 
did not pass into the stomach but escaped through a wound in the 
oesophagus, the taste and odor of food caused a profuse reflex secretion 
of gastric juice, while several other substances fed them failed to have 
any such effect. It is quite possible that bitter tastes may cause this 
reflex secretion in man, and not in the dog, and that the whole effect 
may be explained by the one property common to all these drugs — 
their bitter taste. In addition, it is to be remembered that the im- 
provement is largely subjective, and that the bitters are capable of 
producing a considerable impression upon patients, so that the effects 
may be due in part to suggestion and not to any real action of the drug. 

Action after Absorption. — In very large quantities some of the bitters 
produce effects that are obviously due to their absorption. These have 
seldom been observed in man, but have been studied in animal experiments. 
Thus Compardon states that in many individuals 0.12 G. of quassi in produees 
burning in the throat and stomach, discomfort, headache, nausea, and 
vomiting. In flies and other insects it has a narcotic action. Columbia and 
cetrarin were found by Kohler to increase the blood pressure by stimulation 
of the vasomotor centre when they were injected intravenously. Ramm 
states that the intravenous injection of cetrarin causes irritation of the 
stomach and bowel, purging and vomiting, and general paralysis of the 
central nervous system, which is preceded by convulsions in mammals. He 
did not observe any increase in the blood pressure. Both the glucosides of 
condurango produce in dogs ataxia and loss of coordination, with increased 
movement, and eventually convulsions, and death follows in 12-72 hours or 
longer. The brain seems the part chiefly affected in mammals, although the 
reflex excitability of the spinal cord is also augmented in the frog (Jukna). 
Buxine possesses considerable antiseptic power, and prevents the movement 
of leucocytes and of the lower organisms in the same way as quinine. Large 
doses often cause vomiting, confusion, giddiness and tremor, with diarrhoea 
in dogs, but are sometimes without effect. Aristolockine, which has been 
found in several species of Aristolochia, and probably occurs in the official 
serpentary, produces in rabbits acute necrotic nephritis, with albuminuria 



58 ORGANIC SUBSTANCES ACTING LOCALLY. 

and uraemic symptoms. In dogs it causes a very marked fall of blood pres- 
sure, and hemorrhages in the intestinal mucous membrane, but no nephritis. 
The poisonous aetion of aristolochine is very similar to, but much more 
powerful than that of aloin (Pohl). Lupulinic acid obtained from hops, 
when injected as a neutral salt into the blood, causes first stimulation and 
then paralysis of the medullary centres, but has very little effect when given 
by the stomach even in large doses (Dreser). In beer an oxidized product 
of lupulinic acid occurs, which has no effect even when injected into the 
blood. Berberine is a very widely distributed alkaloid of the pyridine series 
(C 20 H 17 NO 4 ), and when administered in very large quantities per os, causes 
diarrhoea, and occasionally vomiting, tremor, acceleration of the pulse and 
respiration and general weakness, from which the animal recovers only 
slowly. Its subcutaneous or intravenous injection is followed by the same 
symptoms, but paralysis of the hind extremities, convulsions, and asphyxia 
from failure of the respiratory centre may occur when it is administered in 
this way, while the largest quantities are not fatal when exhibited by the 
stomach. The acceleration of the pulse seems due to paralysis of the inhibi- 
tory terminations in the heart, and is accompanied by a fall of blood pres- 
sure from the effects of the alkaloid on the vasomotor centre and on the 
heart directly. Berberine has been credited with causing contraction of the 
uterus and of the spleen, but this is disputed. It has also been said to 
resemble quinine in its effects on bacteria and on the leucocytes, but only in 
very strong solution. Berberine seems to be excreted in part by the kidney 
unchanged, and is said to cause nephritis in large doses. 

The cotoin of Coto bark, and the paracotoin and other constituents of 
Paracoto bark were found by Albertoni to cause dilatation of the intestinal 
vessels when they were injected intravenously or perfused through the mes- 
enteric vessels. Paracotoin is much weaker than cotoin. 

Orexine (C U H 12 N 2 ), an artificial base, seems to stand midway between the 
peppers and the bitters in its action, as it is somewhat more irritating than 
most of the latter. Injected into the frog it induces paralysis, which is ap- 
parently of peripheral origin, and its subcutaneous application in mammals 
is followed by tremor, tonic and clonic convulsions, dyspnoea, acceleration 
of the heart and vomiting. It has some antiseptic action, and tends to form 
methsemoglobin when mixed with the blood. No symptoms have been ob- 
served from its use in man, except increased appetite and augmentation of 
the gastric secretion, and in a few cases a feeling of heat in the throat and 
some nausea. 

Preparations. 

Gentiana (U. S. P.), Gentianae Radix (B. P.), gentian, the root of Genti- 
ana lutea, contains a glucoside, gentiopicrin, a neutral body, gentisin, and 
a trace of tannic acid. 

Extractum Gentians (U. S. P., B. P.), 0.1-0.5 G. (2-10 grs.). 

Extractum Gentianae Fluidum (U. S. P.), 0.5-2 c.c. (10-30 mins.). 

Tinctura Gentians Composita (U. S. P., B. P.), containing gentian, 
bitter orange peel, and cardamom, 2-16 c.c. (|-4 fl. drs.). 

Infusum Gentianae Composition (B. P.), containing gentian , bitter orange 
peel, and fresh lemon peel, |-1 fl. oz. 

Quassia (U. S. P.), Quassiae Lignum (B. P.), the wood of Picrsena excelsa, 
contains several neutral bitter substances, resembling each other closely 
chemically and known as quassiins. 

Extractum Quassia (U. S. P.), 0.05-0.2 G. (1-3 grs.). 

Extractum Quassiae Fluidum (U. S. P.), 0.5-2 c.c. (5-30 mins.). 

Tinctura Quassia (U. S. P., B. P.), 1-4 c.c. (15-60 mins.). 

Liquor Quassiae Concentratus (B. P.), |-1 fl. dr. 

Infusum Quassiae (B. P.), |-1 fl. oz. 

Calumba (U. S. P.), Calumbse Radix (B. P.), columbo, the root of Jateor- 



SIMPLE BITTERS. 59 

rhiza palmata, or Columba, contains columbin, a neutral body, oolumbio 
acid, and the alkaloid berberine. 

Extractum Calumbse Fluidum (U. S. P.), 1-2 c.c. (15-30 mins.). 

Tinctura Calumbse (U. S. P., B. P.), 4-15 c.c. (1-4 fi. drs.). 

Infusum Calumbse (B. P.), ^-1 fl. oz. 

Liquor Calumbse Concentratus (B. P.), |-1 fl. dr. 

Chirata (U. S. P., B. P.), Chiretta, the plant Swertia chirata, contains a 
glucoside, chiratin, and ophelic acid. 

Extractum Chiratse Fluidum (U. S. P.), 0.3-1 c.c. (5-15 mins.). 

Tinctura Chiratse (U. S. P., B. P.), 2-8 c.c. (1-2 li. drs.). 

Liquor Chiratse Concentratus (B. P.), |-1 fl. dr. 

Infusum Chiratse (B. P.), ^-1 fl. oz. 

Taraxacum (IT. S. P.), Taraxaci Radix (B. P.), the root of the dandelion. 
Taraxacum officinale, contains two neutral bitter substances — taraxacin and 
taraxacein. 

Extractum Taraxaci (IT. S. P., B. P.), 0.3-1 G. (5-15 grs.). 

Extractum Taraxaci Fluidum (IT. S. P.), Liquidum (B. P.), 4-12 c c (1-3 
3. drs.). 

Succus Taraxaci (B. P.), 1-2 fl. drs. 

Pareira (U. S. P.), Pareiras Radix (B. P.), the root of Chondrodendron 
bomentosum, contains an alkaloid, buxine. 

Extractum Par eirse Fluidum (IT. S. P.), Liquidum(B. P.), 2-8 c.c. Q-2 fl. drs.). 

Menispermum (U. S. P.), the rhizome and roots of Menispermum cana- 
dense (yellow parilla or Canadian moonseed), contains berberine and meni- 
spermine. 

Extractum Menispermi Fluidum (IT. S. P.), 2-4 c.c. 

Serpentaria (U. S. P.), Serpentarise Rhizoma (B. P.), snake root, the rhi- 
zome and roots of Aristolochia serpentaria and of Aristolochia reticulata. 
contains a volatile oil, an unknown bitter principle, and perhaps an alka- 
loid, aristolochine. 

Extractum Serpentarise Fluidum (IT. S. P.), 1-2 c.c. 

Tinctura Serpentarise (IT. S. P., B. P.), 2-8 c.c. (J-l fl. dr.). 

Liquor Serpentarise Concentratus (B. P.), \-1 fl. drs. 

Infusum Serpentarise (B. P.), J-l fl. oz. 

Humulus (U. S. P.), Lupulus (B. P.), hops, the strobiles of Humulus lupu- 
ius, and Lupulin, a glandular powder separated from hops, contain a volatile 
oil, a bitter neutral substance, lupulin, lupulinic acid, and resins. 

Tinctura Humuli (IT. S. P.), 4-8 c.c. (1-2 fl. drs.). 

Extractum Lupulini Fluidum (IT. S. P.), 2-8 c.c. (£-2 fl. drs.) 

Oleoresina Lupulini (IT. S. P.), 0.1-0.3 G. (2-5 grs.). 

Lupulinum (B. P.), 2-5 grs. 

Infusum Lupuli (B. P.), 1-2 fl. oz. 

Tinctura Lupuli (B. P.), £-1 fl. dr. 

Cusparise Cortex (B. P.), Angostura bark, the dried bark of Cusparia feb- 
rifuga, contains four or more alkaloids, cusparine, cusparidine, galipine, and 
galipidine, along with a volatile oil and a neutral bitter stuff. 

Infusum Cusparise (B. P.), 1-2 fl. oz. 

Liquor Cusparise Concentratus (B. P.), J-l fl. dr. 

Nectandrse Cortex, Bebeeru bark, is not pharmacopoeial, but is occasion- 
ally used in therapeutics. It contains an alkaloid which is now known to be 
buxine, but which has been called beberine, biberine, or bebeerine hitherto. 
Buxine or beberine sulphate is prepared from it. 

Condurango, the bark of Gonolobus condurango, contains two glucosides 
of similar properties, and has been used a good deal of late years a- a stom- 
achic bitter. It was formerly credited with a specific action on epithelioma. 

Cetraric acid, or cetrarin, is obtained from Iceland moss (see page 47), and 
has been recommended as a bitter in doses of about 0.1 (i. (2 grs. >, in tablets. 

Coto bark, whose origin is still doubtful, contains cotoin i< 1 1 ( ' 



60 ORGANIC SUBSTANCES ACTING LOCALLY. 

has been used to form a fluid extract. Dose, 0.3-1.5 c.c. (5-20 mins.). 
Cotoin has been prescribed in the dose of 0.03-0.2 G. (£-3 grs.). 

Orexine Hydrochlorate, C6H4N2C2H3C6H5HCI, is a colorless, crystalline 
body, soluble in about 15 parts of water, with a bitter, somewhat pungent 
taste. It is prescribed in powder or tablets. Dose, 0.3 G. (5 grs.). 

Bael fruit, or Bengal quince, was formerly contained in the B. P., but has 
been omitted in the last edition. Very little is known regarding its action 
or principles, but it may perhaps have some effect as a bitter. 

Many other bitter stomachics might be enumerated, some of which 
have been used largely in former times, but as they are all identical in 
their effects, it seems unnecessary to do so. 

Instead of the simple bitters, cinchona and nux vomica preparations 
are often used in small quantities. Many of the preparations which 
will be enumerated under the volatile oil series owe much of their 
effect to the bitter which accompanies the volatile oil, and in numerous 
other pharmacopoeial preparations bitters are present, although their 
effect is hidden by the action of the drug in other directions. 

Therapeutic Uses. — The bitters are used chiefly to increase the appe- 
tite and the digestion. In convalescents, in persons of sedentary 
habits, and occasionally in chronic dyspeptic conditions they are of 
value, while in cases of more acute gastric irritability they may do 
harm rather than good. Gentian, Quassia, Calumba and Chirata are 
the only simple bitters that are largely used, and the first is much the 
most important. They are generally prescribed as tinctures, fluid ex- 
tracts or other fluid preparations. The three last may be prescribed 
with iron preparations, as they contain little or no tannic acid and 
thus cause no precipitate. Pills are sometimes prescribed with extract 
of gentian or quassia, but it seems open to question whether these in- 
gredients have really any effect when given in this form. Compound 
tincture of gentian is sometimes used to give flavor rather than for any 
effect on the digestion. 

Quassia infusion (ten per cent.) is injected as an enema in the round 
worms of children. 

Several of the drugs mentioned, such as taraxacum and gentian, have been 
supposed to have a specific action on the liver, but there are no sufficient 
grounds for this belief. The supposed virtues of pareira as a diuretic and 
of berberine, buxine, and other alkaloids as substitutes for quinine in ma- 
laria have also proved to have no foundation, and the popular reputation of 
hops as a narcotic probably arises from its association with alcohol in beer. 
Cotoin and Coto bark are said to have some special effect in lessening diar- 
rhoea, in addition to their action as bitters. 

Bibliography. 

Bokai, Reusz, Vas, Huber and Gara. Ungar. Arch, fur Medicin, ii., pp. 295-325. 

Gottlieb. Arch. f. exp. Path., xxxiii., p. 261. 

Brandt. Zts. f. Biol., xxix., p. 277. 

Scanzoni. Ibid., xxxiii., p. 462. 

Farnsteiner. Ibid., xxxiii., p. 475. 

Pawlow and Schumowa-Simanowskaja. Arch. f. [Anat. u.] Phys., 1895, p. 53. 

Binz. Virchow's Arch., xlvi., p. 129. 






/ 1 e 

VOLATILE OIL SERIES. 61 

Jukna. Arb. des pharmak. Institut. Dorpat, iv., p. 81. (Condurango. ) 

Pohl. Arch. f. exp. Path. u. Pharm., xxix., p. 282. ( Aristolochine. j 

Dreser. Ibid., xxiii., p. 129. (Lupnlinic acid.) 

K. v. Bunge. Arb. des pharmak. Institut, Dorpat, xi.-xii., p. 135. (Berberine ) 

Mosseu. Tautz. Ztschr. f. klin. Med., xliii., p. 257. 

Bamm. Historische Studien a. d. pharmak. Instit. Dorpat, ii., p. 1. 

Cornpardon. Bull. gen. deTherap., 1884. 

Albertoni. Arch. f. exp. Path. u. Pharm., xvii., p. 291. (Coto. ) 

Beichmann. Ztschr. f. klin. Med., xiv., p. 177. 

Robert. International Congress Berlin, 1890, iv., p. 58. (Cetrarin ) 

Penzoldt. Therap. Monatsh., 1890, p. 59. (Orexine.) 

Kronfeld. Wiener klin. Woch., 1891, p. 45. (Orexine.) 

V. VOLATILE OIL SERIES. 

The group of volatile, ethereal, or essential oils contains a large 
number of preparations in the pharmacopoeias of all countries. These 
oils are obtained from plants by distillation, or more rarely by pres- 
sure, and must be distinguished by the student from the fatty or fixed 
oils, which are non- volatile. The volatile or ethereal oils are found 
chiefly in the fruits and flowering parts of plants, and are very widely 
diffused through the vegetable kingdom, though some orders, such as 
the LabiataB, Urnbelliferse, Aurantiacese, Cruciferae, and Conifers are 
preeminent in their production. They are all strongly odorous, and 
are therefore used in perfumery, and to conceal nauseous odors and 
tastes in medicine. Their composition is extremely variable. The 
commonest constituents are Terpenes, and some oils contain these 
only, while in a few oils no terpene has been found (Attar of Roses). 
Terpenes are hydrocarbons of the aromatic series, 1 and possess 
the general formula (C 5 H g ) n . The great majority of them, or the 
terpenes proper (C 10 H 16 ), are combinations of a dihydrobenzol with 
propyl and methyl (C 6 H 4 (H 2 )C 3 H 7 CH 3 ). Some twelve terpenes of 
this formula are known, varying in their chemical structure and in 
their stereometrical form. Another group of these hydrocarbons is 
formed by the Sesquiterpenes (C 15 H 24 ), while a few Diterpenes (C„ H 3 .,) 
are known. Some volatile oils consist of these hydrocarbons onlv, but 
many of them contain in addition some oxidized aromatic substances, 
such as phenols, ketones, aldehydes, acids and compounds of these. 
Many of these oxidized products crystallize out when the volatile oil 
is cooled sufficiently, and especially on long standing, and the resulting 
solid is known as a Stearoptene, while the fluid remaining is sometimes 
called Elceoptene. The oils containing oxygen are not so volatile as the 
pure hydrocarbons, but the odor is often due chiefly to the oxidized 
substances. A very few oils contain nitrogenous bodies, generally in 
the form of cyanides, while on the other hand, the majority of the vola- 
tile oils of the Cruciferse contain sulphur bodies, which lend them a 
pungent, disagreeable odor, quite different from that of the other <>il-. 

l Of late years several oxidized products have been isolated from the volatile oils, 
which belong not to the aromatic but to the fatty series, and from these hydrocarbons 
have been formed resembling the terpenes closely in general, but differing from them in 
belonging to the fatty series. No ''fatty terpene" has as yet been shewn to occur in 
nature, but the presence of these oxidized forms renders their existence in plants 
extremely probable. 



62 ORGANIC SUBSTANCES ACTING LOCALLY. 

The volatile oils are generally clear, colorless fluids, although some 
of them are green from the presence of small quantities of vegetable 
coloring matter, while others are blue in color from the presence of a 
terpene derivative (azulene). After long keeping they often acquire 
a yellowish color and an acid reaction, from the formation of resins. 
They are generally light, sparkling fluids, but the oils of copaiva and 
cubebs are more viscid. They are insoluble in water except in very 
small amount, which, however, is enough to lend their characteristic 
odor to the solution ; in strong alcohol, ether, benzol, chloroform, and 
fixed oils, they are freely soluble. 

Many of the plants from which the volatile oils are obtained possess 
other active constituents, such as bitters, and as many of the prepara- 
tions used in therapeutics are formed, not from the distilled oils, but 
from the crude parts of plants, it must be noted that the oil is not the 
only active principle in them. A series containing members which 
differ so widely chemically, and which in fact have only their volatility 
and their aromatic nucleus in common, could not be expected to have 
a uniform action in the animal organism. It is found, however, that 
they resemble each other in their therapeutic properties, because they 
are used almost solely for their local action, and that in only small 
quantities. Some of the volatile oil preparations which are employed 
for their general effects, will be discussed later. (See Camphor.) 

Action Externally. — The volatile oils all possess antiseptic properties, 
which are doubtless due in part to their volatility enabling them to 
penetrate readily into protoplasm and to lessen its vitality by acting 
as foreign bodies. In addition, they are nearly related to the benzol 
series, the members of which are all antiseptics and protoplasm poisons. 
They differ a good deal in their germicidal power, and are much more 
poisonous to the moulds than to the bacteria. The most active oils 
are those containing a large amount of terpene, such as the oil of tur- 
pentine. 

Their volatility may also explain their irritant action in part, for 
most other volatile substances are more or less irritant, but here again 
their relation to the phenols and benzol cannot be ignored. Applied 
to the skin, they cause redness, itching and warmth, owing to a local 
dilation of the vessels, which may be due to the penetration of the oil 
to the cutaneous arterioles or veins, or to a reflex from the irritated 
terminations of the sensory nerves acting on the vasomotor centres. 

When painted on the mucous membranes, such as those of the eye 
or nose, or on wounds, the volatile oils cause similar irritation, which 
is betrayed by redness and congestion, pain and smarting. 

Action on the Alimentary Canal. — Strong solutions of the oils act 
as irritants in the mouth. They have generally a hot, burning taste, 
and if kept in the mouth, cause redness and irritation of the mucous 
membranes, although some of them induce a sense of coolness at first. 
At the same time the organs of smell are affected by these oils, which 
are almost all possessed of characteristic odors. The irritatioa £>f the 
mouth leads to a reflex secretion of saliva, which is often very profuse. 



1 



VOLATILE OIL SERIES. 63 

The antiseptic action of the oils is exercised in the mouth as elsewhere, 
and may have a beneficial effect in some conditions. 

On passing into the stomach, the oils cause the same sensation of 
warmth in that organ, and this is accompanied by a sense of well- 
being and comfort, the appetite is often increased, and any feeling of 
distention after meals is relieved. This is often attended by the eruc- 
tation of quantities of gas. Substances which produce these effects in 
the stomach are known as carminatives, and many explanations of their 
action have been offered. The oils undoubtedly act as antiseptics here 
as elsewhere, and may hinder the development of yeasts and other 
organisms and thus be of benefit, but this would not give the imme- 
diate feeling of relief which is often experienced after a small quantity 
of these remedies. The process of digestion seems to be rather re- 
tarded than accelerated by the presence of the oils, as far as can be 
judged by test-tube experiments and by some measurements made by 
Buchheim on the digestion of animals with gastric fistula?. The secre- 
tion of the gastric glands has been said to be increased by the direct 
action of the volatile oils, but this has been disputed. But it must 
not be forgotten that the most powerful stimulant to gastric secretion 
is the smell and taste of food, and that substances of agreeable taste 
and odor cause a marked increase in the gastric juice by reflexes from 
the mouth and nose. An argument for the direct action of the volatile 
oils on the secretory glands has been drawn from the observation that, 
applied to the frog's skin, they induce a profuse local secretion, but this 
is scarcely sufficient basis for an explanation. The eructation of gas 
certainly suggests that the volatile oils accelerate the movements of the 
stomach, and this has been repeatedly confirmed by r the direct observa- 
tion of the stomach walls. Brandl has also shown recently that absorp- 
tion occurs much more rapidly from the stomach in the presence of 
slight irritants, such as the volatile oils. Finally it must be added that 
many of the beneficial effects are purely subjective ; the patient has a 
feeling of warmth and comfort in the region of the stomach, arising 
from the slight irritation and consequent hyperemia of the mucous 
membrane, but this does not necessarily indicate any marked altera- 
tion in the processes of digestion or in the movements of the stomach. 

Similar effects are believed to be produced in the intestine, for the 
administration of these oils is often followed by an improvement in its 
condition, manifested by lessened flatulence and distention, and relief is 
given by their use in some forms of colic. The antiseptic action may 
play a part in these effects. Scanzoni and Farnsteiner have recently 
shown that the intestine, like the stomach, absorbs more rapidly in the 
presence of small quantities of the oils. The pancreatic secretion was 
supposed to be increased by their irritant action in the stomach, through 
a reflex travelling both centripetally and centrifugally along the vagus 
fibres (Gottlieb), but Schirokikh asserts that this is true only when 
large quantities produce very marked gastric irritation. Whether the 
peristaHic movements of the bowel are increased by the volatile oils 
is quite unknown. It is believed, however, that their administration 



64 ORGANIC SUBSTANCES ACTING LOCALLY. 

lessens the pain and griping produced by some of the more powerful 
purgatives, and several pharmacopoeial preparations are formed on this 
theory, which is supported by many years of clinical experience. 

A considerable increase in the leucocytes of the blood follows their 
ingestion by the mouth, but this is observed in congestion of the 
stomach and intestine from other causes and is not induced by the sub- 
cutaneous or intravenous injection of the volatile oils, so that it cannot 
be regarded as a specific effect. Wiuternitz found that irritation of 
the pleura causes less purulent exudate in animals treated with some 
volatile oils than in controls which were not treated in any way, and 
concludes that the presence of the oils in the blood lessens the exudate 
and also promotes its absorption ; he is inclined to regard this anti- 
phlogistic action as a result of the leucocytosis and of a supposed attrac- 
tion exercised on the leucocytes by the oils, which prevents their wander- 
ing into the tissues. 

Excretion. — Like other bodies of the aromatic series, they tend to 
undergo a partial oxidation in the body ; thus the terpenes (C 10 H 1C ) 
become terpenols (C 10 H lr> OH), and several derivatives of the terpenes 
have been shown to undergo a similar change of a hydrogen atom to 
hydroxyl, while others which contain the -OH group originally, remain 
unaltered. The odor of the original oil or of these derivatives may often 
be detected in the breath, showing that a small part is excreted by the 
lungs, and possibly traces may be eliminated by the skin. Some also 
escapes by the kidney uncombined and imparts an odor to the urine 
either of the original oil or of some oxygen derivative ; for instance, 
oil of eucalyptus or of turpentine give the urine a violet odor. But 
much of the hydroxyl product is combined with glycuronic acid and 
escapes in the urine in this form, while some may combine to form 
conjugate sulphates. The glycuronic acid reduces Fehling's solution, 
especially when the urine is previously boiled with acid, so that the 
volatile oils were formerly credited with inducing glycosuria. Some 
of the constituents of the oils are oxidized to acids and excreted in the 
urine as salts. 

In the course of excretion, some of the oils cause irritation of the 
lungs and kidneys, so that some of them are employed to increase the 
bronchial secretion, while others have a distinct diuretic action. This 
irritant action is of course not confined to the tissue, but extends to 
microbial guests, so that the volatile oils have been given internally 
with the intention of destroying or retarding the growth of bacteria in 
the lungs, and some of them are used almost exclusively for their anti- 
septic action in the urine. 

Poisoning. — The various oils differ a good deal in their activity, 
while resembling each other closely in the general characters of their 
effects. All of them may produce marked irritation of the stomach 
and bowel when given in large quantities, but the oils of tansy, sage, 
and English pennyroyal are distinguished especially by. the violent in- 
flammation they cause, and by the frequency with which fatal poison- 
ing occurs from their use. The terpenes appear to be but slightly 



VOLATILE OIL SERIES. 65 

poisonous, and their effects are probably limited to local irritation ; the 
oxidized aromatic substances have been shown to be the poisonous con- 
stituents in all the oils hitherto examined. The symptoms are those 
of acute gastric, intestinal, and often renal irritation — vomiting, purg- 
ing, acute pain in the abdomen, blood in the stools and in the vomited 
matter, collapse, weakness of the pulse and respiration, anuria, or 
albumin and blood in the urine, and convulsive attacks ending in coma 
and death. Great hyperemia of the abdominal organs, often blood in 
the peritoneal cavity, and sometimes acute inflammation of the kidney 
are the chief post-mortem appearances. The hyperemia and conges- 
tion of the organs of the abdomen may cause abortion in pregnancy, or 
increase the menses, and in the majority of cases of poisoning, these 
oils have been taken with the object of inducing abortion. In many 
instances, however, the drug has proved fatal without this end being 
achieved. 

General Action. — The small quantities of volatile oils administered in or- 
dinary medicinal use pass through the tissues without modifying them per- 
ceptibly, their only effects arising in the organs by which they are absorbed 
and excreted. In large quantities, however, some of them (the oils of worm- 
wood, nutmeg, sage, savine among others) produce symptoms which indi- 
cate an affection of the central nervous system quite apart from their local 
action. The latter also produces nervous effects reflexly, and it has been 
found exceedingly difficult to distinguish these indirect results from those 
caused by the direct action on the central nervous system. A good deal of 
divergence is to be found in the statements of different writers from this cause, 
and also from the fact that comparatively few researches have been carried 
out with pure principles. Many of the oils vary in their constituents accord- 
ing to the climate, the season of the year, and other conditions under which 
the plant was grown, and some of the confusion may arise from differences 
in the oils used by investigators. Almost all the oils hitherto examined cause 
depression and final paralysis in the frog. The action seems to be mainly on 
the brain, larger quantities being required to paralyze the spinal cord than to 
prevent all spontaneous movements. This stage of depression is preceded 
by one of excitement after oil of wormwood and some others. Some of the 
oils paralyze the terminations of the motor nerves in voluntary muscle like 
curara and camphor. 

In mammals the general action of the constituents of the volatile oils seems 
to involve a preliminary stimulation and subsequent depression of the nerve 
cells. The relative importance of these two stages differs in different oils, 
some, e. g., turpentine oil, causing only a transient excitement, followed by 
marked weakness and depression, while others, such as the oil of absinth, 
cause very marked excitement and convulsions. The activity of the oils 
as nervous poisons also varies greatly, some producing only insignificant 
effects on the central nervous system compared with those from their local 
action, while in others, such as the oil of absinth or wormwood, the symp- 
toms from the nervous system predominate in cases of poisoning. A- a 
general rule the higher divisions of the central axis are affected more than 
the lower. Few of the oils, save absinthol, cause any marked increase in 
the reflexes, which are also comparatively slightly affected during the stage 
of depression. The stimulation of the brain causes convulsions of different 
kinds, of which the epileptiform fits, seen after absinth, have been examined 
by Boyce. He found that, while the action on the cerebrum was mainly 
responsible for these convulsions, other parts of the central nervous system 
were also involved, although it was impossible to assign to each its precise 
5 



66 ORGANIC SUBSTANCES ACTING LOCALLY. 

share in the disturbance. Some of the oils, e. g., saffrol and nutmeg oil, 
produce tremors similar to those described under carbolic acid, and pre- 
sumably of similar origin. In many cases a combination of excitement and 
ataxia is observed, the animal moving about restlessly, but being unable to 
balance itself. Clonic convulsions are also observed among their effect-, 
probably from excessive stimulation of the mid-brain. In the later stages of 
poisoning the spontaneous movements cease, while the excitation of the 
lower centres still persists, and wild convulsive movements accompany the 
final arrest of the respiration. 

The medullary centres are also affected differently by the various oils and 
their constituents. The respiration is finally depressed by all of them, but 
this depression is often preceded by stimulation, the breathing increasing 
both in rapidity and in volume. The vasomotor centre undergoes similar 
changes, the blood-pressure falling from some oils immediately, from others 
only after a preliminary increase. 

The heart does not seem to be affected by most of the volatile oils, except 
indirectly. In cases of poisoning the collapse and shock may alter the 
character of its contractions, but direct effects on the cardiac muscle have 
not been shown to be produced by the volatile oils, unless when enormous 
quantities are injected intravenously. 

Heffter and Lindemann have recently shown that some of the constituents 
of the oils cause fatty degeneration of various organs, especially of the liver 
and kidney, while others of very similar constitution have no such effect. 

Large quantities of the volatile oils often produce a considerable fall in the 
temperature. 

Although these general effects of the volatile oils have no therapeutic im- 
portance, the frequent occurrence of epilepsy and insanity in habitual ab- 
sinth drinkers have given them some practical interest. 

Different oils are used for different purposes in therapeutics, although 
they all resemble each other in most respects, and it is, therefore, con- 
venient to divide them into several therapeutic classes. 1 A number 
of the less irritant members are used very largely as flavoring agents, 
for their carminative effects on the stomach and intestine, more rarely 
as antiseptics, and as expectorants. Another small class may be formed 
of the malodorous oils, a third of those used as genito-urinary disin- 
fectants, while several which contain a large proportion of terpenes and 
are too irritant to be employed as carminatives, will be discussed among 
the skin irritants. 



1. Volatile Oils Used as Flavoring Agents and Carminatives. 

As regards their use as flavoring agents but little need be said, one 
preparation is used by one physician, another by another, and the se- 
lection is largely a matter of custom and taste. The orange prepara- 
tions are probably more generally appreciated by patients than any 
others. Carminatives are used only when no marked irritation of the 
stomach or intestine is present, in cases where the gastric juice seems 
unable to cope with the food ingested, especially in persons of sedentary 
habits. In cases of colic, flatulence and abdominal distention they are 
often of use, provided that these are not due to peritonitis and other 

x Two small and unimportant groups of bodies which are used for the same purposes 
as some of the volatile oils have been inserted along with these. 



_ 



VOLATILE OIL SERIES. 07 

inflammatory diseases. Several of them have been employed as sur- 
gical antiseptics, notably thymol, but its insolubility in water has pre- 
vented its extensive adoption ; they are more widely used as parasiti- 
cides for scabies, pediculi, etc. Some of the oils, such as oil of cloves, 
are used in dentistry to relieve pain, and also for their antiseptic action ; 
the relief of pain is due to their paralyzing the exposed nerve ends 
after a preliminary irritation. Eucalyptus has been advised in septic 
conditions and in malaria, and at one time was supposed to be a spe- 
cific for the latter ; it improves some cases, but is not reliable, and 
has probably no more effect than others of the series. Its use as an 
internal remedy in septicemia is apparently no more successful, al- 
though it still enjoys some reputation in these cases. Volatile oil 
preparations are sometimes given internally in the hope that in their 
excretion through the lungs they will exercise an antiseptic action in 
pulmonary disease, but the traces excreted in this way are quite incap- 
able of any noticeable effect on microbial growth and the tubercle bacil- 
lus, against which these measures are most frequently directed, appears 
to be peculiarly resistant to the action of this group of remedies. 
They are frequently inhaled with a similar object. Some of them have 
been used as anthelmintics to destroy tapeworm in the intestine, but 
they are less efficient than some other remedies, unless given in quanti- 
ties which are liable to irritate the stomach and bowel. Externally 
some of them are used as mild skin irritants, generally in the form of 
spirits. Arnica has a great popular reputation as a stimulating local 
remedy in bruises and sprains, although it has no specific action and is 
in no way preferable to the other members of the series. 

The volatile oils are important constituents of many of the popular 
liqueurs, such as Kummel, Maraschino, Curacoa, Chartreuse, etc., and 
therefore have a certain dietetic importance. 

Preparations. 

Crude Drugs. — Many of the pharmacopoeial preparations are whole plants, 
seeds, leaves or flowers, and are never prescribed, although some of them 
are used in popular medicine in the form of infusions or ' ' teas. ' ' The virtues 
of these old-fashioned remedies lie perhaps more in the large draughts of 
warm water than in the traces of volatile oil which they contain, but the 
presence of the latter prevent, to some extent, the nausea produced by warm 
water alone. These infusions are used to induce perspiration in fevers or 
chills, as diuretics, or to relieve colic and griping-, and generally contain 
about a tablespoonful of the herb to one or two cupfuls of water. Those 
most frequently used for this purpose are peppermint and spearmint leaves 
and tops (Mentha Piperita and Mentha Viridis, U. S. P.); Coriander 
(Coriandrum, IT. S P., Coriandri Fructus, B. P.) ; Chamomile flowers (Anthc- 
mis, U. S. P., Anthemidis Flores, B. P., and Matricaria, IT. S. P.): Anise 
(Anisum, U. S. P., Anisi Fructus, B. P., the fruit of Pimpinella anisum); 
Elderflower (Sambucus, U. S. P., Sambuci Flores, B. P.); Horehound (Marru- 
bium, IT. S. P., leaves and tops); and Balm (leaves and tops of Melissa offici- 
nalis, U. S. P.). In different countries, however, the constituents of the 
herbalist recipes vary according to the local flora. Tin 1 V. S. Pharmaco- 
poeia recognizes a number of other crude drugs of this group, but as these 
are seldom or never prescribed, they need only be enumerated here : 



68 ORGANIC SUBSTANCES ACTING LOCALLY. 

Centifolia and Rosa Gallica (white and red rose petals), Eucalyptus, Limonis 
Cortex (lemon peel), Aurantii Dulcis Cortex, Aurantii Amari Cortex (sweet and 
bitter orange peel), Caryophyllus (eloves), Pimenta (allspice), Cinnamomum 
(cinnamon), Sassafras (sassafras bark), Cypripedium (lady's slipper), Illicivm 
(star anise), Fveniculum (fennel), Vanilla (vanilla), Cardamomum (cardamom;. 
Carum (caraway), Melissa (balm), Myristica (nutmeg), Macis (mace), Tanace- 
tum (tansy), Hedeoma (pennyroyal), Salvia (sage), Sabina (savine), Arnica, 
Absinthium (wormwood), Allium (garlic), and Zingiber (ginger). The British 
Pharmacopoeia is less lavishly supplied with these little used crude drugs. 
It contains, in addition to those first mentioned: Rosas Gallica Petala (red 
rose petals), Limonis Cortex (lemon peel), Aurantii Cortex Rccens and Siceatus 
(fresh and dried orange peel), Caryophyllum (cloves), Carui Fructus (caraway 
seeds), Pimenta (alispice), Cinnamomi Cortex (cinnamon bark), Sassafras Radix 
(sassafras root), Funiculi Fructus (fennel seeds), Cardamomi Sernina (cardamom 
seeds), Myristica (nutmeg), Arnicae Rhizoma (arnica rhizome), Zingiber (gin- 
ger), and Anethi Fructus (dill). 

Bitter Almonds (Amygdala Amara, U. S. P., B. P.) may be mentioned 
here, as, although they contain no volatile oil in themselves, one is formed 
from them when they are bruised in water. They contain a glucosido, 
amygdalin, and a ferment, emulsin, which, in the presence of water, decom- 
poses the amygdalin into dextrose, prussic acid, and benzaldehyde. 

Amygdalin. Dextrose. Prussic acid. Benzaldehyde. 

C 20 H 27 NO U + 3H 2 = 2(C 6 H 12 6 ) + HCN + C 7 H 6 + H 2 

The prussic acid and benzaldehyde, wiiich are probably in combination and 
not merely mixed together, are known as the oil of bitter almonds, which 
is much more poisonous than the other volatile oils, owing to its containing 
prussic acid. Emulsin is also contained in the sweet almond, but no amyg- 
dalin, so that no prussic acid is formed when it is pounded in water. The 
fixed oil of almonds is formed from bitter and sweet almonds, but contains 
no prussic acid. Laurel leaves (Laurocerasi Folia, B. P.), and the bark of 
the Virginian prune, or cherry (Prunus Virginiana, U. S. P., Pruni Virgini- 
anse Cortex, B. P'.), also contain amygdalin, or some nearly related substance, 
and emulsin, and form benzaldehyde and prussic acid when rubbed up with 
water. The Virginian cherry bark has, however, a more bitter taste than 
the others, from the presence of a resin or some other unknown body. 

The Volatile Oils themselves are also represented in unnecessarily large 
numbers in the pharmacopoeias. 

U. S. P. — Oleum Menthse Piperitse (oil of peppermint), 01. Menthae Viridis 
(spearmint oil), 01. Gaultherise (wintergreen), 01. Lavandulae Florum (oil of 
lavender), 01. Eucalypti (eucalyptus oil), 01. Limonis Corticis (oil of lemon), 
01. Aurantii Corticis (oil of orange peel), 01. Aurantii Florum (oil of orange 
blossom, oil of Neroli), Oleoresina Zingiberis (ginger), 01. Amygdalae Amarae 
(bitter almonds), 01. Caryophylli (oil of cloves), 01. Pimentse (oil of allspice), 
01. Carui (caraway oil), 01. Cinnamomi (cinnamon), 01. Coriandri (coriander), 
01. Erigerontis (erigeron or fieabane), 01. Cajuputi (cajuput), 01. Bergamottae 
(bergamot), 01. Sassafras (sassafras) 01. Anisi (anise), 01. Foeniculi (fennel), 
01. Myrciae (bay), 01. Rosmarini (rosemary), 01. Hedeomae (pennyroyal), 01. 
Juniperi (juniper), 01. Sabinae (savine), 01. Rosas (oil, attar or otto of roses), 
01. Betulae Volatile (volatile oil of birch), 01. Thymi (thyme), 01. Myristicae 
(nutmeg). 

B. P. — Oleum Anethi (oil of dill), 01. Anisi (anise), 01. Cajuputi (cajuput). 
01. Carui (caraway), 01. Caryophylli (cloves), 01. Cinnamomi (cinnamon), 01. 
Coriandri (coriander), 01. Eucalypti (eucalyptus), 01. Lavandulae (lavender), 
01. Limonis (lemon), 01. Menthae Piperitae (peppermint), 01. Menthae Viridis 
(spearmint), 01. Myristicae (nutmeg), 01. Anthemidis (chamomile), 01. Pimentaz 
(allspice), 01. Rosae (oil, attar, or otto of roses), 01. Rosmarini (rosemary) 

The majority of these oils resemble each other very closely in their effects 






VOLATILE OIL SERIES. 69 

and require no special comment. Oil of roses is so expensive that it is never 
used in medicine, especially as it has no special advantages over the others. 
The oils of rosemary, juniper, and savine are more irritant than the others, 
and are seldom used. The oils of wintergreen and of birch consist mainly 
of methyl-salicylate, and may be used instead of the other salicylates. 
Nutmeg and mace oils are more poisonous than the others, not from their 
local irritant action so much as from their effects after absorption. Oil of 
bitter almonds contains a very variable amount of prussic acid and therefore 
cannot be substituted for the other volatile oils, but its preparations are so 
dilute as to be void of all danger. 

The volatile oils themselves are comparatively little used. A single drop 
may be added to powders, pills or solutions to give a pleasa.it odor, and 
their presence in tooth powders renders these more or less strongly antiseptic. 
Occasionally they are given in cases of colic or in chill by pouring a lew- 
drops on a piece of sugar which is sucked. The dose of the volatile oils in 
general is 1-2 drops. 

Spiritus are formed from many of the volatile oils by dissolving them 
in alcohol, sometimes with the addition of water and sometimes with 
some of the crude drug, so that the preparation is really a mixture of 
tincture and spirit. The spirits or essences of the volatile oils are used 
very largely as flavoring agents in mixtures for internal use, and are 
often added to external applications to lend them odor. They may 
also be prescribed where alcohol is indicated but is distasteful to the 
patient ; the spirits of the volatile oils contain nearly double the 
amount of alcohol in brandy, and have to be diluted accordingly. 
Any of them may be used as carminatives, but the spirits of pepper- 
mint, cinnamon, anise and lavender are more frequently used for this 
purpose than the others. Spirit of juniper is often given as a diuretic, 
either alone or along with other drugs. Spirit of rosemary is generally 
used externally. Many of the common perfumes are spirits of differ- 
ent volatile oils ; thus eau de Cologne contains the oils of bergamot, 
lemon, rosemary, lavender and orange-flower, along with acetic ether 
and alcohol. 

The dose of the spiritus as carminatives is 1-4 c.c. (15-60 mins.). 
They are often prescribed along with other stomachics, such as mix 
vomica, cinchona, or the bitters. 

U. S. P. — Spiritus Amygdalae Amarse, Spir. Anisi, Spir. Aurantii Compositus 
(containing the oils of orange peel, lemon, coriander and anise), Spir. Cinna- 
momi, Spir. Gaultherise, Spir. Juniperi, Spir. Juniperi Compositus (containing 
oils of juniper, caraway and fennel. Dose, 4-8 c.c, 1-2 fl. drs.), Spir. Lavan- 
dulae, Spir. Limonis, Spir. Menthse Piperitae, Spir. Menthae Viridis, Spir. Myrcix 
(bay rum, containing oils of bay, orange peel and allspice), Spir. Myristicse. 

Elixir Aromaticum is a preparation of the Spir. Aurantii Compositus. which 
is used exclusively as a flavor. 

B. P. — Spiritus Anisi, Sp. Cajuputi, Sp. Cinnamomi, Sp. Juniperi. Sp. La- 
vandulae, Sp. Menthse Piperitae, Sp. Myristicse, Sp. Rosmarini. 

The compound spirit of horseradish (Spir. Armoracise Compositus) is ob- 
tained by extracting the volatile oils of horseradish, bitter-orange peel, and 
nutmeg with dilute alcohol and purifying them by distillation. Horseradish 
oil, like that of most of the Cruciferre, is a sulphur compound, and has a 
peculiarly hot, burning taste. Dose, 1-2 fl. drs. (4-8 c.c). 



70 ORGANIC SUBSTANCES ACTING LOCALLY. 

Aquae. — The volatile oils are very insoluble in water, but when they 
are shaken in it, enough remains in the water to give it the odor and 
taste of the oil. In the process of obtaining the oils from the crude 
drugs by distillation, some oil is held by the water, and a number of 
these waters (aquae) are contained in the pharmacopoeias. They are used 
as substitutes for distilled water in making up prescriptions, the small 
quantity of volatile oil serving merely to give a pleasant odor and taste. 

U. S. P. — Aqua Anisi, Aq. Aurantii Flor. and Aq. Aurantii Florum Fortior 
(the latter containing twice as much volatile oil as the former), Aq. Cinna- 
momi, Aq. Fceniculi, Aq. Menth. Piperitse, Aq. Menth. Viridis, Aq. Bosse, 
Aq. Bosse Fortior (the latter twice as strong as the ordinarily used Aq. 
Bosse). 

B. P. — Aqua Anethi, Aq. Anisi, Aq. Aurantii Florum, Aq. Carui, Aq. Cin- 
namomi, Aq. Fceniculi, Aq. Laurocerasi (laurel water, containing prussic acid 
and benzaldehyde), Aq. Menthse Piperitse, Aq. Menthse Viridis, Aq. Pimentse, 
Aq. Bosse, Aq. Sambuci. 

Other preparations containing volatile oils merely as flavoring ingredients 
are Trochisci Menthse Piperitse, U. S. P. (peppermint lozenges), and Unguen- 
tum Aquse Bosse (cold cream), U. S. P., B. P. 

Some of the preparations containing volatile oils are derived not 
from the oil itself, but from the crude drug, and therefore contain 
non-volatile substances Avhich are generally absent from the prepara- 
tions already mentioned. As a general rule these non-volatile bodies 
are inactive, but in some cases, bitters or resins are contained in the 
preparations, and may influence their action. Thus a bitter glucoside, 
hesperidin, is found in the orange peel, and is present in the prepara- 
tions formed directly from it, while it is absent from those formed from 
the volatile oil. Ginger contains a resin of hot, burning taste, which 
increases the carminative action of the oil. Cinnamon contains some 
tannic acid, which passes over in the tincture, while a fixed oil is con- 
tained in cardamom. Arnica contains a bitter substance, arnicin ; 
calamus, a bitter, acorin, in addition to a volatile oil ; cascarilla, a 
bitter principle, cascarillin, along with another oil. Preparations 
which contain a bitter substance in addition to a volatile oil, are often 
classed as aromatic bitters along with the Pepper series. 

Among the preparations formed from the crude drugs are the Syrups, 
which are used exclusively as flavoring agents. 

U. S. P. — Syrupus Aurantii Florum, Syr. Amygdalse, Syr. Aurantii, Syr. 
Bosse, Syr. Zingiberis, Syr. Pruni Virginianse. 

B. P. — Syrupus Aromaticus (containing tincture of orange and cinnamon 
water), Syr. Aurantii, Syr. Aurantii Floris, Syr. Limonis, Syr. Pruni Virgini- 
anse, Syr. Bosse, Syr. Zingiberis. Dose of syrups, B. P., 2-4 c.c. Q-l fl. dr.). 

The Tinctures are used for the same purposes as the spirits of the 
pure oils, and in the same dose, 1-4 c.c. (15-60 mins.). The tinctures 
of arnica are employed externally as applications to bruised surfaces 
and in similar conditions, but they have no more effect than other 
preparations, although they are popularly regarded as specifics. 



VOLATILE OIL SERIES. 71 

U. S. P. — Tinctura Arnicas Florum, Tinct. Arnica? Radicis, Tinct. Aurantii 
Amari, Tinct. Aurantii Dulcis, Tinct. Cardamomi, Tinct. Cardamom i Composite 
(contains cardamom, cinnamon, caraway), Tinct. Cinnamomi, Tinct. Lavan- 
dulae Composita (oils of lavender, rosemary, cinnamon, cloves, nutmeg), Tinct. 
Vanillas, Tinct. Zingiberis. 

B. P. — Tinctura Arnicas, Tinct. Aurantii, Tinct. Cardamomi Composita (con- 
taining cardamom, caraway, cinnamon and raisins), Tinct. Cinnamon,;. 
Tinct. Lavandulae Composita (lavender, rosemary, cinnamon, nutmeg), Tinct, 
Limonis, Tinct. Pruni Virginianas, Tinct. Zingiberis, Tinct. Cascarillas. 

Fluid Extracts of the volatile oil series. 

U. S. P. — Extractum Arnicse Radicis Fluidum. 

Ext. Aurantii Amari FL, 1-2 c.c. (15-30 mins.). 

Ext. Rosas FL, 4-8 c.c. (1-2 fl. drs.). 

Ext. Calami FL, 0.5-1.3 c.c. (8-20 mins.). 

Ext. Sabinas FL, 0.2-0.5 c.c. (3-8 mins.). 

Ext. Pruni Virginianas FL, 2-4 c.c. (h-1 fl. dr.). 

Ext. Zingiberis FL, 0.5-1.3 c.c. (8-20"mins.). 

Ext. Aromaticum FL, 0.5-1.3 c.c. (8-20 mins.), from aromatic powder. 

The only fluid extracts at all extensively used are the last three. 

Infusions. 

U. S. P. — Infusum Pruni Virginians. 

B. P. — Infusum Aurantii. 

Infusum Aurantii Compositum (formed from bitter orange peel, fresh lemon 
peel and cloves). 

Infusum Caryophylli. 

Infusum Rosas Acidum (containing sulphuric acid). 

Infusum Cascarillas. 

These infusions are given in doses of \-\ fl. oz. (15-30 c.c.) and may be 
used instead of the medicated waters (aquse). 

Other Preparations. 

Extractum Arnicas Radicis (IT. S. P.) is used to form the Emplastrum Arnicas 
(U. S. P.), Arnica plaster. 

Extractum Anthemidis (B. P.), 0.1-0.5 G. (2-8 grs.). 

Confectio Rosas Gdllicas (B. P.). 

These two last preparations are used almost exclusively as cohesive bases 
for pills. 

Pulvis Aromaticus (U. S. P.) contains cinnamon, cardamom, ginger, and 
nutmeg in powder, and is a useful carminative in doses of 0.3-2 G. (5-30 grs.). 

Pulvis Cinnamomi Compositus (B. P.) contains cinnamon, cardamom and 
ginger, and is used as a carminative in doses of 10-40 grs. 

Unguentum Eucalypti (B. P.). 

Several pure substances which have been isolated from the volatile 
oils and introduced into therapeutics (eucalyptol, menthol, thymol) will 
be mentioned later. (See index.) 

A number of other volatile substances are used locally in medicine 
for the same purpose as the volatile oils, although they are classified in 
other groups owing to their possessing other properties which arc not 
shared by the oils. Among these may be mentioned especially the 
preparations of chloroform (aqua, emulsum, spiritus, linimentum), the 
simple and compound spirits of ether, and acetic ether. These arc used 
largely for the same purposes as the volatile oil preparations, and when 
administered in moderate quantities do not cause any further effects. 
The preparations of alcohol known as spirits, or liqueurs, or essences, 



72 ORGANIC SUBSTANCES ACTING LOCALLY. 

contain volatile oils — Curacoa, Cherrywater (Kirch wasser), Kummel, 
Essence of Mint, etc. — and the simpler spirits, Brandy, Whiskey, 
Rum, Gin, and the wines contain bodies known as oenanthic ethers, 
which probably act in a similar way. 

Bibliography. 

Bucholtz. Arch. f. exp. Path. u. Pharra., iv., p. 1. (Antiseptic action. ) 

Bokorny. Arch. f. d. ges. Physiol., lxxiii., p. 555. 

Binz. Arch. f. exp. Path. u. Pharm., v., p. 109 ; viii., p. 50. 

Pohl. Ibid., xxv., p. 51. 

Batelli. Trav. du Labor, de Therapeut. de Geneve, iii., p. 197. 

Brandl, Scanzoni, Farnsteiner. Ztschr. f. Biol., xxix., p. 277, xxxiii., pp. 462, 475. 
(Action on absorption from stomach and bowel ; compare papers by PawLow and his 
pupils. Arch, des Scienc. biolog., ii. and iii.) 

Beffter. Arch. f. exp. Path. u. Pharm., xxxv., p. 342. (Saffrol, etc.) 

Winternitz. Ibid., xlv., p. 163. 

Frornmu. Hildebrandt. Ztschr. f. physiol. Chem., xxxiii., p. 579. 

Lindemann. Arch. f. exp. Path. u. Pharm., xlii., p. 356; Ztsch. f. Biol., xxxix., 
p. 1. 

Bohm. Inang. Diss., Halle, 1879. (Absinth.) 

Boyee. Brit. Med. Journ., 1893, ii., p. 1097. (Absinth.) 

Magnan. Comptes Kendus de l'Academie, lxviii., p. 825. (Absinth.) 

Lapin. Inaug. Diss., Dorpat, 1893. (01. Menth. pip.) 

Fleischmann. Untersuch. d. Wiirzburger pharmakol. lnstitut, iii., p. 50. (Turpen- 
tine. ) 

Robert Centralbl. f. d. med. Wissen., 1877, p. 129. (Turpentine.) 

Hare. Medical News, li., p. 593. (Turpentine.) 

Pallop. Inaug. Diss., Dorpat, 1889. (Turpentine.) 

Wallace. J. of Exp. Med., vi. (Nutmeg.) 

2. Pepper Group. 

Several drugs which act as carminatives like the volatile oils, but which 
differ from them in the nature of their active constituents, may be mentioned 
here. 

Black Pepper contains a weakly basic substance, Piperine (which is broken 
up by caustic alkalies into Piperidine and Piperinic acid), in addition to a 
volatile oil and a bitter pungent resin. According to Buchheim a second 
base, Chavicine, also exists in it and can be decomposed into Piperidine and 
Chavicic acid. Piperine is insoluble in water, and has therefore no taste 
when absolutely pure, but is hot and pungent to the taste when it is taken in 
solution. 

Pyrethrum, or pellitory, contains similar constituents, volatile oil, resin 
and Pyrethrine, which is decomposed into Piperidine and Pyrethric acid 
(Buchheim). 

The unstable alkaloid, Sedine, of Sedum acre (biting stonecrop), resembles 
the pepper alkaloids in its effects, but has not been accurately examined as 
yet. 

Capsicum, or Cayenne pepper, contains a number of ill-defined, non-vola- 
ti'e bodies, which have been termed Capsicol, Capsaicin, Capsicin, etc., but 
of which little or nothing is known accurately. As it has no volatile oil, it 
differs entirely from the other members of the series, but it acts similarly in 
the stomach, and is used frequently as an irritating carminative. 

Ginger might also be included here, as it owes its pungency in part to the 
presence of a resin along with the volatile oil. 

The volatile oils derived from the Cruciferse differ from the others in con- 
taining sulphur, and in possessing a much more irritating action. Thus the 
volatile oil of mustard might be treated of along with the peppers rather 
than with the other volatile carminatives, but mustard is used in medicine 



VOLATILE OIL SERIES. 73 

only as a skin irritant, and will be taken up in that connection (see page 89). 
The horseradish (Armoracia, B. P.) and the formerly official scurvy- grass 
(Cochlearia officinalis) are used as carminatives, and owe their activity to 
their containing similar or identical sulphur compounds. 

These drugs differ from the volatile oils only in being more irritant when 
applied to the skin and alimentary canal. The absorption of large quanti- 
ties has led to inflammation of the kidney in some instances. 

Pepper and capsicum are largely used as condiments, and are compara- 
tively seldom prescribed in therapeutics. Both are used in domestic medi- 
cine as skin irritants, and capsicum is prescribed where a strong stomachic 
irritant is required. The tincture has been employed in chronic alcoholism 
in order to provide a substitute for the local irritant effects of spirits in the 
stomach. Ginger preparations are added to other remedies as flavoring 
agents, the syrup being generally used, and they are also among the best of 
the carminatives. The lozenges are prescribed in chronic inflammatory con- 
ditions of the pharynx and larynx. Pyrethrum is rarely employed. Piper- 
ine has been advised in malaria as a substitute for, or adjuvant to quinine, 
but has fallen into disuse. Pepper has been administered internally as a 
genito-urinary disinfectant and stimulant. 

Preparations. 

Piper (IT. g. p.), Piper Nigrum (B. P.), black pepper, the unripe fruit of 
Piper Nigrum. 

Oleoresina Piperis (TJ. S. P.), 0.03-0.1 c.c. (|-2 mins.). 

Piperinum (TJ. S. P.), 0.1-0.5 G. (2-3 grs.)/ 

Confectio Piperis (B. P.), 60-120 grs. 

Pyrethrum (IT. S. P.), Pyrethri Radix (B. P.), pellitory, the root of Ana- 
cyclus Pvrethum. 

Tinctura Pyrethri (TJ. S. P., B. P.). 

Zingiber (TJ. S. P., B. P.), ginger, the rhizome of Zingiber officinale. 

Syrupus Zingiberis (TJ. S. P., B. P.), 4-8 c.c. (1-2 fl. dr.). 

Tinctura Zingiberis (TJ. S. P., B. P.), 2-4 c.c. (|-1 fl. dr.). 

Extractum Zingiberis Fluidum (TJ. S. P.), 0.5-1 c.c. (5-15 mins.). 

Oleoresina Zingiberis (TJ. S. P.), 0.05-0.1 c.c. (1-2 mins.). 

Trochisci Zingiberis (TJ. S. P.). 

Capsicum^ Cayenne pepper, chillies, the fruit of Capsicum fastigiatum 
(TJ. S. P.); Capsici Fructus, the dried fruit of Capsicum minimum (B. P.). 

Tinctura Capsici (TJ. S. P., B. P.), 1-2 c.c. (15-30 mins.). 

Oleoresina Capsici (TJ. S. P.), 0.01-0.05 c.c. (^-1 min.). 

Extractum Capsici Fluidum (TJ. S. P.), 0.03-0.1 c.c. Q— 2 mins.). 

Emplastrum Capsici (TJ. S. P.). 

Unguentum Capsici (B. P.). 

Armoraciae Radix (B. P.), horseradish root, the fresh root of Cochlearia 
Armoracia. 

Spiritus Armoracise Compositus (B. P.), 1-2 fl. drs. (See p. 68.) 

Piper Methisticum, or Kava Kava, is used in the South Sea Islands to 
prepare an intoxicating liquor, which according to Kesteven, differs from 
the alcoholic preparations in producing marked muscular weakness without 
affecting the mental powers. Other observers state, however, that it causes 
confusion and sleep very much as alcohol does. Its local action resembles 
that of pepper, and like it, it has been advised in gonorrhoea. Its virtues 
seem to reside in two resinous bodies. 



Bibliography. 

Buchheim. Arch. f. exp. Path. u. Pharm., v., p. 455. 
Jungst. Ibid., xxiv., p. 315. 
Hogyes. Ibid., ix., p. 117. 



74 ORGANIC SUBSTANCES ACTING LOCALLY. 

Kesteven. Practitioner, xxviii., p. 199. 
Lewin. Berlin, klin. Woch., 1886, p. 7. 
Cerna. Therapeut. Gazette, 1891, p. 7. 

3. Malodorous Volatile Oils. 

Some of the volatile oils differ from the others in possessing an odor 
which is disagreeable and nauseating to most people, although not to 
all. The best known of these are the Oils of Asafwtida and Valerian. 
The former occurs along with resins and gums exuding from some 
species of Ferula, and contains several organic sulphur compounds, to 
which it owes its odor. Oil of Valerian, 1 from Valeriana officinalis, 
is almost without odor when freshly distilled, but when kept for some 
time and exposed to the air, it assumes a somewhat unpleasant, pene- 
trating odor. It contains two terpenes, borneo-camphor, and numer- 
ous esters of formic, acetic and valerianic acid. While both of these 
oils are generally regarded as possessing very unpleasant odors, asa- 
fcetida is used in India as a condiment, and valerian was formerly used 
in England as a perfume. Another species of Ferula which is in- 
cluded in the pharmacopoeias, but of which little is known, is Sumbul, 
the root of Ferula Sumbul. It has a strong musk-like odor, and is 
sometimes used to adulterate musk. 

Asafcetida and valerian are used in hysterical affections, and the 
benefits accruing from their administration have generally been at- 
tributed to the mental impression produced by their unpleasant odor 
and taste, and not to any action they produce after absorption. 

But Kionka and Liebrecht 2 state that valerian has a definite stimu- 
lating action on the psychical functions and that this is due to the 
presence of certain valerianic compounds in the oil. They have also 
formed some artificial compounds ( Valyl) possessing similar properties. 
The ordinary valerianic salts have no further effects than other salts 
of the acetic acid series, so that it is quite irrational to use such bodies 
as valerianate of quinine for their action in hysteria. 

Asafcetida is also used like the other volatile oils as a carminative 
and as an expectorant, and the emulsion is given by the mouth or in 
an enema to relieve abdominal distention. 

Preparations. 

Asafcetida (U. S. P.), a mixture of volatile oil, gum, and resin from Ferula 
fcetida. 

Emulsum Asafcetida, 15-30 c.c. (|— 1 fl. oz.). 

Pilulse Asafcetidse, 1-3 pills. 

Tinctura Asafcetidse, 2-4 c.c. (30-60 mins.). 

Pilulse Aloes et Asafcetidse, 2-5 pills (used largely in hysteria with consti- 
pation). 

Asafetida (B. P.), a gum-resin obtained from the root of Ferula fcetida 
and probably other species. 

Tinctura Asafetidse, \-l fl. dr. 

Pilula Aloes et Asafetidse, 4-8 grs. 

1 Sikorsha, These de Geneve, 1899. 
2 Deutsch med. Woch., 1901, Dec. 5. 




VOLATILE OIL SERIES. 75 

Pilula Galbani Composita, 4-8 grs. 

Spiritus Ammonise Fetidus, 20-40 niins. for repeated administration • for a 
single administration 60-90 mins. 

Valeriana (U. S. P.), Valerianae Radix (B. P.), valerian, the rhizome and 
roots of Valeriana officinalis. 

Extractum Valerianae Fluidum (U. S. P.), 2-4 c.c. (^-1 fl. dr.). 

Tinctura Valeriana (U. S. P.), 5-10 c.c. (1-3 fl. dr."). 

Tinctura Valerianae Ammoniata (U. S. P.), 5-10 c.c. (1-3 fl. dr.). 

Tinctura Valerianae Ammoniata (B. P.), \— 1 fl. dr. 

Sumbul (U. S. P.), Sumbul Radix (B. P.), the root of Ferula Sumbul 

Tinctura Sumbul (U. S. P., B. P.), |-1 fl.'dr. 

4. Volatile Oils Used as Genito- urinary Disinfectants. 

Another group of volatile oils is used chiefly for geuito-uri nary dis- 
infection. The best known of these are the Oils of Copaiba, Cubebs and 
Sandalwood, which resemble each other closely in character. Oil of 
cubebs and oil of copaiba contain a large proportion of sesquiterpene 
(C 15 H 24 ), and the oil of sandalwood has two oxidized substances (san- 
tolol and santalal), which can be reduced to a sesquiterpene identical 
with that of copaiba. In copaiba the volatile oil is associated with 
one or more resinous acids, and in cubebs there is in addition to resi- 
nous acids a bitter substance, Cubebin, which, however, is not absorbed 
from the stomach and bowel, and is entirely inactive. Cubebs and 
copaiba have long been used as genito-urinary disinfectants, while 
sandalwood oil is a more recent addition to the group, which is less 
disagreeable to take and has less tendency to disturb the digestion. 1 
The oils have the ordinary effects on the skin, stomach and intestine, 
are absorbed, and are excreted partly by the lungs, but chiefly by the 
kidneys in combination with glycuronic acid ; some oil is unchanged, 
some is partially oxidized in the tissues. 

The products of the oils excreted in the urine appear to have some 
antiseptic action for the urine of persons treated with them putrefies 
more slowly than ordinary urine and the growth of many of the more 
common germs is somewhat retarded by it. On the other hand there 
seems some question as to how far it is destructive to the gonococcus, 
which sometimes grows readily in culture media made up with such 
urine instead of water. AVinternitz therefore attributes the undoubted 
therapeutic efficacy of these oils to their lessening the inflammatory 
exudate rather than to their antiseptic action, without denying that the 
latter may also be of some importance. In large quantities, these 
oils cause irritation in the bladder and urethra, which leads to a con- 
stant desire to micturate, and to much pain and difficulty in doing so : 
sometimes the pain is so great as to lead to complete retention. \\ hen 
the urethra or bladder is in a state of inflammation, these symptoms 
are produced by even small doses, so that these oils are generally 
avoided in the acute stages of inflammation, and only given later when 

'The ideal genito-urinary disinfectant of this series ought to be well borne by the 
stomach and bowel, and ought to be excreted mainly by the kidneys in a fairly strong 
combination with glycuronic acid, as, if the latter is easily split on in the urine, it is 
liable to act as a culture medium for bacteria. (Schmiedebei g 



76 ORGANIC SUBSTANCES ACTING LOCALLY. 

the disease has passed into the subacute or chronic stage. They are 
used in some inflammatory affections of the bladder, but much more 
extensively in gonorrhoea. 

Copaiba and cubebs both contain resinous acids in addition to the 
volatile oil, and these possess considerable diuretic powers, and are 
also credited, along with the oils, with some action on the bronchial 
mucous membrane, so that they often form constituents of "expec- 
torant" mixtures, prescribed to lessen the secretion of the bronchi. 
These resins are excreted in the urine, and are precipitated by the ad- 
dition of acids ; when the nitric acid tests for albumin are employed 
after copaiba, a precipitate is accordingly obtained, and may be mis- 
taken for albumin, but can easily be distinguished from it by the addi- 
tion of alcohol, which redissolves the resin but not the proteid. The 
urine is often found to reduce Fehling's solution, in some cases ap- 
parently from the presence of sugar, in others from the glycuronic acid 
combined with the oil. The oil of sandalwood is excreted more 
rapidly than the others. Copaiba and cubebs are less irritant to the 
stomach than many of the other volatile oils, but after their prolonged 
administration (especially in the case of copaiba) symptoms of gastric 
disturbance sometimes appear in loss of appetite and uneasiness in the 
stomach. Sandalwood oil is said to be less irritant than the others. 
Occasionally skin eruptions occur after the use of these oils ; they are 
generally of the nature of urticaria, sometimes of erythema nodosum, 
and only very rarely is eczema seen. The cause of these skin erup- 
tions is unknown, but they may be due to the gastric disturbance. 

Preparations. 

Copaiba (U. S. P., B. P.), Balsam of Copaiba, Copaiva, the oleoresin of 
Copaiba Langsdorffii and of other species of Copaifera. Dose, 0.5-1.3 c.c. 
(10-20 mins.), B. P., |-1 fl. dr. 

Massa Copaibse (U. S. P.), formed from the oleoresin by the addition of 
magnesia ; an inferior preparation. 

Oleum Copaiba (U. S. P., B. P.), the oil freed from the resin by distilla- 
tion, 0.5-1 c.c. (10-15 mins.). 

Resina Copaibse (U. S. P.), 1 G. (15 grs.). 

Cubeba (U. S. P.), Cubebae Fructus (B. P.), Cubebs, the unripe fruit of 
Piper Cubeba, 2-8 G. (30-120 grs.) in powder. 

Extractum Cabebse Fluidum (U. S. P.), 0.5-2 c.c. (10-30 mins.). 

Oleoresina Cubeba (U. S. P.), 0.5-1 c.c. (10-15 mins.). 

Tinctura Cubebse (U. S. P., B P.), 4-8 c.c. (1-2 fl. drs.). 

Oleum Cubeba (U. S. P., B. P.), 0.5-1 c c. (10-15 mins.). 

Trochisci Cubebse (U S. P.). 

Oleum Santali (U. S. P., B. P.), Sandalwood oil, distilled from the wood 
of Santalum Album. Dose, 0.5-1 c.c. (10-15 mins.). 

Therapeutic Uses. — As has been mentioned, these drugs find their 
most extensive application in the subacute stages of cystitis and gonor- 
rhoea. They are also used in bronchial disease with an excessive flow 
of mucopurulent secretion ; less often copaiba is prescribed along with 
other diuretics to promote the secretion of urine. The cubeb lozenges 



VOLATILE OIL SERIES. 77 

are sucked in hoarseness and relaxed sore throat, and often give relief 
owing to the pungent stimulating action. 

In gonorrhoea the therapeutic agent is undoubtedly the volatile oil, 
the resin having little or no antiseptic action. The oils and the oleo- 
resins are often administered in capsules, as they have an unpleasant 
odor and taste, especially those of eopaiba. They may also be given as 
emulsions, and cubebs is sometimes prescribed as a powder suspended 
in mucilage. The resin of copaiba is rarely used alone. 

Several other oils have been used as substitutes for Copaiba and Cubebs. 
Among these may be mentioned Gurjun Balsam, which is obtained from 
Dipterocarpus alatus, and contains a sesquiterpene and a resin. It has been 
used in gonorrhoea and as a local application in leprosy. 

Matico, the dried tops of Piper angustifolium, which contains a volatile 
oil, resin and acid, has also been used in gonorrhoea to some extent. 

Its pharmacopceial preparations are 

Extractum Matico Fluidum (U. S. P.), 1-3 c.c. (15-45 mins.). 

Tinctura Matico (U. S. P.), 4-8 c.c. (1-2 fl. drs.). 

Bibliography. 

Berriatzik. Yierteljahrschrift f. prakt. Heilkunde, lxxxi., p. 9, and c, p. 239. 

Schmidt. Arch. d. Pharm., cxci., p. 1. 

Quincke. Arch. f. exp. Path. u. Pharm., xvii., p. 273. 

Heffter. Ibid., xxxv., p. 369. 

Winternitz. Ibid., xlv., p. 163. 

Karo. Ibid., xlvi., p. 242. 

See also the bibliography of the volatile oils in general. 

5. Uva Ursi (Arbutin). 

A number of drugs which are used for almost the same purposes as the 
cubebs series, but which do not all owe their activity to volatile oils, may 
be mentioned here. 

Uva Ursi. — The leaves of the bearberry, Arctostaphylos Uva- Ursi, and of 
allied plants contain two glucosides, Arbutin and Methylarbuiin, along with 
large quantities of tannin, an inactive glucoside, Ericolin, and a neutral in- 
soluble body, Urson. These glucosides are decomposed by the action of 
acids or of emuisin into glucose and hydroquinone or rnethylhydroquinone, 
bodies of the benzol series. A part of the arbutin administered in thera- 
peutics seems to undergo this decomposition in the body, but most of it is 
eliminated by the kidneys unchanged. It is possible that the small quantity 
of hydroquinone and methylhydroquinone which appears in the urine is 
formed from arbutin by the bacteria of the intestine, and not by the activity 
of the tissues. 

Uva ursi is found to have some diuretic action, which is obviously due to 
its acting on the renal epithelium, and the urine is found to undergo 
putrefaction much more slowly than usual. This was at one time believed 
to be due to the formation of hydroquinone, but it seems more likely that 
arbutin itself is a slight stimulant to the renal cells, and that it is also 
weakly antiseptic. It is still undecided how far the other constituents of 
uva ursi are active, but there is little doubt that the arbutin and methyl- 
arbutin are the chief principles. 

The urine is often dark in color after uva ursi or arbutin. and this tint 
deepens when it is allowed to stand and undergo putrefaction. The color- 
ation is due to the hydroquinone, which is subject to further oxidation, and 
forms brownish-green pigments similar to those seen in the mine after 
carbolic acid and its allies. When decomposition of the urine occurs in the 



78 ORGANIC SUBSTANCES ACTING LOCALLY. 

bladder, as in cystitis, the urine may have this dark color when passed. In 
these cases probably less of the arbutin escapes uudecomposed, but this has 
not been demonstrated. 

Large quantities of uva ursi cause nausea, vomiting and diarrhoea, but 
Lewin states that this disturbance of the alimentary canal may be avoided 
by filtering the watery jjreparations through animal charcoal, or by admin- 
istering the glucosides instead of the cruder preparations. 

Buchu, the leaves of several species of Barosma, contain a volatile oil, 
one constituent of which is a camphor body, Diosphenol. This volatile oil 
is absorbed and is excreted by the kidneys, and renders the urine slightly 
antiseptic. It does not increase the renal activity appreciably. 

Pichi, the twigs of Fabiana imbricata, contains a resinous acid, a gluco- 
side and traces of an alkaloid, none of which have been satisfactorily exam- 
ined. It has been found of benefit in the same conditions as Buchu and 
Uva Ursi. 

Zea, or cornsilk, contains a resinous acid which increases the secretion of 
urine by direct stimulation of the renal epithelium. 

Chimaphila, or pipsissewa, contains a volatile substance, Chimaphilin, and 
arbutin, and is used as a substitute for Uva ursi. 

Preparations. 

Uva Ursi (U. S. P.), Uvse Ursi Folia (B. P.), the leaves of Arctostaphylos 
Uva-ursi (bearberry). 

Extractum Uvse Ursi (U. S. P.), 1-4 G. (15-60 grs.). 

Extractum Uvse Ursi Fluidum (U. S. P.), 5-15 c.c. (1-4 fl. drs.). 

Infusum Uvse Ursi (B. P.), J-l fl. oz. 

Buchu (U. S. P.), Buchu Folia (B. P.), the leaves of Barosma betulinaand 
B. crenulata. 

Extractum Buchu Fluidum (U. S. P.), 2-4 c.c. (30-60 mins.). 

Tinctura Buchu (B. P.), \-l fl. dr. 

Infusum Buchu (B. P.), 1-2 fl. oz. 

Zea (U. S. P.), cornsilk, the styles and stigmas of Zea Mays (Indian corn 
or maize). 

Extractum Zese Fluidum (U. S. P.), 5-10 c.c. (1-2 fl. drs.). 

Chimaphila (U. S. P.), Pipsissewa, the leaves of Chimaphila umbellata. 

Extractum Chimaphilse Fluidum (U. S. P.), 2-5 c.c. (£-1 fl. dr.). 

Fabiana (Pichi), the branches of Fabiana imbricata (not pharmacopceial). 

Extractum Fabianse Fluidum, 4 c.c. (1 fl. dr.). 

Arbutin has been advised as an improvement on the crude Uva ursi. It 
is given in doses of 1-4 G., in sweetened solution. 

Therapeutic Uses. — These drugs are all used as mild disinfectants of the 
urinary tract, and are generally prescribed along with more powerful 
diuretics. They are found to give relief in catarrh and inflammation of the 
bladder. 

Bibliography of Uva Ursi. 

Lewin. Virchow's Archiv, xcii.,p. 521. 
Fasciitis. Wiener Med. Presse, 1884, p. 398. 
Kunkel. Munch, med. Wc-ch., 1886, p. 891. 

VI. SKIN IRRITANTS AND COUNTER-IRRITATION. 

The practice of applying irritants to the skin in internal diseases is 
one of great antiquity. The theories on which this therapeutic method 
is based have changed with the advance of medical knowledge, until, 
no explanation satisfactory to modern scepticism being forthcoming, 
the use of these remedies has fallen into a certain disrepute in the 






SKIN IRRITANTS AND COUNTER-IRRITATION 79 

last few years. The old theory of revulsion or derivation was at first 
based on the belief that disease was a malignant entity or humor 
which might be drawn from the deeper organs to the surface by means 
of irritation of the skin. Later, it was supposed that the congestion 
of the diseased organs might be relieved by the withdrawal of fluid to 
the skin, and this belief has been held in more or less modified forms 
in quite modern times. In addition, it was recognized very early that 
irritation of the skin relieved pain in many instances. The means by 
which the skin irritation was attained, were extremely numerous and 
varied ; large numbers of drugs have been used, and in addition me- 
chanical devices of all kinds were employed, such as burning, electri- 
cal currents, or the introduction of setons. In many of these the idea 
of irritation was combined with that of leaving a way of escape for 
humors. This latter is only of historical interest, but the practice of 
relieving internal organs by external irritation or counter-irritation per- 
sists still, and perhaps merits more attention than it receives at the 
hands of many physicians. 

The effects of an irritant applied to the skin are local and remote. 
The first symptoms of irritation are congestion and redness of the 
part, and many drugs which produce only this degree of irritation in 
ordinary circumstances, are known as Rubefacients. Stronger irritants 
cause blistering, and are called Vesicants, while some drugs which 
cause irritation and small discrete suppurations, receive the names of 
Pustulants. 

Local Symptoms. — The application of an irritant to the skin causes 
a feeling of warmth, and often of itching, which may later become 
intensified into actual pain. The skin becomes red, congested, warm, 
and at first is more sensitive to touch and painful stimuli, though the 
sensitiveness is afterwards lessened. This condition persists for a 
longer or shorter time according to the nature of the irritant, and then 
passes off slowly. Very often desquamation follows, if the rubefacient 
has acted for some length of time. Stronger irritation is followed at 
first by the same results, but soon small globules of fluid appear below 
the epidermis, and these coalesce so as to form a large accumulation 
of fluid, which raises the epidermis completely off the true skin, form- 
ing a blister. If the irritant be removed, the fluid of the blister un- 
dergoes a slow absorption, so that in the course of a few days the epi- 
dermis forms an empty sack, which, however, is not obliterated by the 
adhesions of the walls. If the blister be opened, the sensitive dermis 
is exposed, and the secretion of fluid continues for some time, until a 
new epidermis has been formed. 

The distinct and separate points of inflammation caused by the 
pustulants are due to their affecting the orifices of the skin glands ami 
not the intervening tissue. This has been ascribed in some instances 
to the drug being rendered irritant at these points by the presence oi 
acids formed by the decomposition of the sebum and perspiration ; a 
simpler explanation is that the pustulants cannot pass through the 
horny epidermis, but act as irritants wherever they come in contact 



80 ORGANIC SUBSTANCES ACTING LOCALLY. 

with living tissue, that is, at the orifice of the glands. They cause 
the same sensation of warmth and prickling of the skin as the other 
irritants, but even in the earlier stages of their action small, dark-red, 
raised points are observed, exactly as in some of the exanthemata, and 
these afterwards form small abscesses. If the application be persisted 
in, these discrete abscesses may burst through the intervening tissues 
and become confluent, and large abscesses have thus been formed in 
the skin. When the irritant is removed before the formation of pus, 
the inflammation of the ducts slowly subsides and the epidermis peels 
off as after the milder irritants. 

The local effects of the rubefacients and vesicants are identical with 
those of acute inflammation. The pain and discomfort are due to the 
action on the nerve terminations, while the redness and swelling be- 
tray the local dilatation of the vessels. This latter is perhaps due to 
the direct effect of the irritant on the vessel walls, rather than to any 
reflex action from the irritation of the sensory nerves, but it cannot be 
said to be known how far this latter agency is involved in the result. 
The dilatation of the vessels and the slowing of the blood current in 
them lead to the transudation of fluid and leucocytes into the tissues, 
especially at the points where the irritation is greatest, and the accu- 
mulation eventually pushes off the horny epidermal layer from the 
living layers and forms a blister. The fluid in the blister has been 
shown to contain some of the irritant, which diffuses into it through 
the epidermis. The oedema and swelling is not confined to the skin, 
but extends into the subcutaneous tissue and the more superficial layers 
of muscle. 

If the irritation be continued long enough, suppuration may com- 
mence in the blister and lead to deep erosion of the tissues. 1 

Remote Action. — Local irritation cannot exist without causing cer- 
tain general changes which affect the whole organism. These arise 
from the reflex stimulation of various centres in the medulla oblongata, 
and are thought to explain many of the beneficial effects of counter- 
irritation. The centres involved are those regulating the heart, the 
tone of the vessels, and the respiration. Moderate irritation of the 
skin causes an acceleration of the heart-rhythm, which has not been 
satisfactorily explained, while more powerful irritation slows the heart 
through the inhibitory centre. The blood-pressure measured in the 
arteries is considerably increased by ordinary irritation of the skin, 
but if it be very severe or widespread, the slowness of the pulse may 
cause a fall of tension. This increase in the blood-pressure is due to 
the reflex stimulation of the vasomotor centre, which causes a constric- 
tion of the arterioles over wide areas of the body. The constriction 
is not general, however, but seems to affect the abdominal organs 

1 Samuel states that when the rabbit's ear has recovered from the local irritation in- 
duced by croton oil, it is not so readily acted upon by this poison again. This he as- 
cribes to some change in the blood vessels, which acquire a toleration for the irritant. 
It is not determined whether this holds good for other irritating drugs, nor, in fact, 
whether it is generally true for croton oil. 



SKIN IRRITANTS AND COUNTER-IRRITATION. 81 

chiefly, while the vessels of the limbs and probably those of the skin 
are not contracted. The result is that while the blood-pressure is 
raised equally throughout the body, the resistance to the circulation is 
greater in the abdominal organs than in the rest of the body, and more 
blood is accordingly supplied to the muscles and skin and less to the 
internal organs than normally. 

The effects of skin irritation on the respiration are less uniform. In 
the rabbit the breathing is sometimes accelerated, sometimes slowed by 
mild stimulation, while stronger stimuli seem to slow it always. The 
effect of the application of skin irritants on the respiration in man has 
not been observed accurately, but that sudden stimulation of the skin 
causes gasping and irregularity of the respiration, may be observed 
whenever cold water comes in contact with the more sensitive parts of 
the body. 

The temperature of the body also undergoes changes when the skin 
is irritated. When the irritation is slight, an increase in the rectal 
temperature is often observed at first, while a decrease follows later, 
but on powerful stimulation, the preliminary rise of temperature is so 
short as to escape observation by ordinary methods, while the subse- 
quent fall is more distinct and prolonged. The skin temperature is 
raised at the same time as the internal temperature falls. The expla- 
nation of these changes in the internal and external temperatures is 
obviously the altered distribution of the blood, more of which 
flows through the skin vessels and is cooled than usual. This results 
in a fall of the internal temperature and a rise in that of the skin, 
through the warm blood from the interior of the body pouring through 
the superficial vessels. The preliminary rise in the temperature has 
not been explained. The whole subject of the alteration of the tem- 
perature through counter-irritation has perhaps received greater atten- 
tion than it deserves, if the observations of Jacobson be correct, for 
he found the variations in man to amount to less than one-tenth of a 
degree Centigrade as a general rule. 

The metabolism has been found to be altered by the application of 
irritants to the skin, and, although in the experiments on which this 
statement is based, the surface exposed to the irritant was larger than 
that affected in therapeutics, it seems probable that some change is pro- 
duced by the ordinary agents also. Zuntz and Rohrig found that bath- 
ing animals in strong salt solution increased the oxygen absorbed and 
the carbonic acid excreted much more than bathing in ordinary water, 
and Paalzow obtained the same result from the application of mustard 
plaster. The nitrogen of the urine is also said to be increased. This 
increase in the oxidation of the tissues is of the same nature as that pro- 
duced by cold, and is due to an augmentation of the muscular activity, 
which, however, is too slight to cause any perceptible movement. 

Irritation of the skin induces leucocytosis in the same way as irrita- 
tion of the alimentary canal. This is especially evident after the 
application of a vesicant such as cantharides plaster, while rubefaction 
seems to have less effect. The injection of irritants into the subcutane- 
6 



82 ORGANIC SUBSTANCES ACTING LOCALLY. 

ous tissues induces a leucocytosis similar to that following can- 
tharides. 

Lastly, in considering the effects of skin irritation on the general 
vitality, it may be mentioned that a sudden application may awake the 
consciousness, as is seen in the effects of dashing cold water on the 
chest, or of striking the hands in narcotic poisoning. Another example 
is seen in the improved mental condition so often observed in fever 
patients treated with cold baths. This improvement is due to the 
changes in the skin, and not, as is often said, to the fall in temperature, 
for the latter is often insignificant. 

In rabbits, irritation of the skin causes albuminuria, but this is elic- 
ited easily in these animals by a large variety of procedures. In the 
guinea-pig, an animal in which the nervous centres seem to be more 
easily deranged than in most others, irritation of the skin produces 
very profound and often fatal changes, through reflex excitation of 
inhibitory areas of the brain (Roger). 

All of these effects are produced by irritation at any point of the 
surface, and are quite insufficient to explain the practical use of counter- 
irritants to affect a particular organ. For example, in gastric disor- 
ders a counter-irritant is often applied just over the ensiform cartilage, 
while in facial neuralgia a blister behind the ear often gives relief. If 
the beneficial results were due to the general alteration of the circula- 
tion, respiration, or temperature, there would be no reason to vary the 
point of application, for the effect would not vary. Zuelzer, there- 
fore, attempted to ascertain whether the deeper tissues and the internal 
organs were affected by superficial irritation over them, and found 
that when cantharides was applied to one side of a rabbit's back 
for fourteen days, the superficial muscles under it w r ere congested, 
while the deeper layers and the lung were anaemic when compared 
with the corresponding parts on the other side. His treatment, how- 
ever, led to necrosis and suppuration, so that his conclusions are not 
unimpeachable. Lazarus-Barlow and Philipps observed recently that 
the muscles on the same side as, but at some distance from a blister, 
were of higher specific gravity than those on the uninjured side, while 
those immediately below the blister were of lower specific gravity, and 
therefore concluded that fluid was drawn from the deeper muscles to 
supply the superficial ones. This, however, evidently requires that 
the internal organs to be affected must be not only contiguous, but 
also continuous with those directly affected, and offers no explanation 
of the alleged effects of irritation of the skin upon the stomach or 
lungs. Much light has been thrown on the subject by the researches 
of Head, who found that in many cases internal disease is accom- 
panied by a tenderness of the skin, and mapped out with care the skin 
areas corresponding to each organ. In this way he was able to show 
that a distinct relation exists between irritation of an internal organ 
and that part of the skin which is supplied by the same segment of 
the spinal cord or brain. Thus in painful diseases of the stomach, ten- 
derness is often complained of in the skin of the epigastrium, while in 



SKIN IRRITANTS AND COUNTER-IRRITATION. 



S3 



oesophageal stricture, pain is often referred to a point near the angle of 
the scapula and to another in the neighborhood of the apex-beat. 
The superficial points are, of course, only connected with the dig 
organ by means of nerve-fibres, but Head's observations show that a 
nervous impulse from these organs dues not pass in an indeterminate 
manner through the central nervous system, but has a distinct tendency 
to affect the superficial areas which are supplied with sensory nerves 
from the same segment of the cord. It would, therefore, seem a plaus- 
ible theory that an affection of these superficial areas may affect the 

Fig. 1. 




The right side is divided into segments which correspond to some of the skin areas in which TIcad 
found tenderness in internal diseases. 1. Area of tenderness in disease of the lungs 2. Ln diseases 
of the stomach. 3. In ovarian disease. 4. In disease of the Fallopian tuhes and other appendages. 



On the^left side are represented the points of application of counter-irritants in disease of the lungs 
(A), of the stomach {B), of the ovary (C), and of the uterine appendages (V). 

corresponding internal organ more than the rest of the body, and this 
is exactly what is required to explain the benefits derived from the use 
of counter-irritants. It is especially noticeable that several of the 
points which Head observed to be affected by internal disease are 
precisely those points at which experience has shown irritation to 
be most beneficial. (Fig. 1.) Thus the application of a blister over 
the epigastrium has long been recognized as a means of relieving gas- 
tric disorders. Similarly the old treatment of iritis by means of a 
blister on the temple may be justified by the fact that Head found 
areas of tenderness on the temple accompanying this disease. 



84 ORGANIC SUBSTANCES ACTING LOCALLY. 

The exact nature of the effects of counter-irritation on the internal 
organs has not been ascertained, but it would seem most probable that 
an alteration in the calibre of the vessels and in the sensory nerves or 
their terminations is induced. These alterations may, however, pro- 
duce or be accompanied by a distinct alteration in the activity of the 
organs ; for example, there seems good reason to believe that in many 
cases irritants applied to the abdomen produce evacuation of the bowels. 

Besides these physiological effects of counter-irritation, it must not 
be forgotten that a great impression is produced on the patient, and 
that some of the benefit may be due to hypnotic suggestion. 

Therapeutic Uses. — Local irritants are applied occasionally to pro- 
duce an alteration in the nutrition and blood supply of the skin itself 
and of the subcutaneous tissues. Thus in some chronic inflammatory 
conditions, with effusions into, or indurations of the subcutaneous tis- 
sues, the improvement of the circulation produced by slight irritation 
may be of benefit. An example of this is the treatment of ulcers of 
old standing with irritants. Another case in which a slight inflamma- 
tory attack causes very obvious improvement, is in corneal opacity, 
which may be removed entirely in some cases by the acute inflam- 
matory reaction produced by such irritants as abrin. Probably a 
similar effect is produced on subcutaneous effusions, as in bruises. 
Some interesting experiments on this subject have recently been per- 
formed by Wechsberg, who induced suppuration in both hind legs of 
rabbits by the injection of irritants and then treated the one leg by the 
application of various irritants to the skin, while the other was left 
untreated as a control. He invariably found the abscess of the leg 
subjected to treatment less extensive and showing a greater tendency 
to heal than the other, and accounts for this by the oedema induced by 
the skin irritant diluting the original irritant and promoting its 
absorption. The increased blood supply must lead to a larger number 
of leucocytes and more alexines around the inflammation than would 
otherwise be present. He found that the absorption of pigments from the 
rabbit's ear was much accelerated by the application of irritants to the 
skin over the part, and cites this as evidence that irritants are 
absorbed more rapidly under similar treatment. For these purposes 
only the milder irritants are required ; in fact, vesication may do more 
harm than good. Mild irritation alters the sensitiveness of the sen- 
sory organs of the skin, and heat is often applied to alleviate pain and 
discomfort in the skin itself. In other instances pain is increased by 
heat, and, in fact, it is sometimes applied in the treatment of local 
anaesthesia, with the object of rendering the surface more sensitive. 
In many forms of skin disease, mild irritants are found to be of bene- 
fit ; this is sometimes attributed to their antiseptic action, but the 
slight irritation is undoubtedly of some importance. 

Counter-irritants are used in a large number of diseases, often with- 
out any definite idea of what precise effects they will elicit, but merely 
because they have been found to give relief in similar conditions. As a 
general rule they are placed over the affected organ, and this corre- 



SKIN IRRITANTS AND COUNTER-IRRITATION. 85 

sponds fairly in most cases of disease of the trunk with Head's area of 
skin tenderness. In the head, however, the segmental arrangement 
has been rendered very irregular by the compression in development, 
and counter-irritants are often found to be most effective when placed 
at some distance from the seat of pain, e. g., behind the ear in soi in- 
forms of facial neuralgia. They are used in acute inflammation of the 
lungs and pleura, in gastric disorders accompanied by much pain, in 
colic and in neuralgia and neuritis. Their action is very uncertain, but 
their application is often followed by great relief, more especially of 
pain. They are also used occasionally in shock or collapse, not for 
their effect on any individual organ, but to elicit the reflex alterations 
in the circulation which have already been described. A blister is 
often recommended in internal haemorrhage, and may very possibly 
lessen the bleeding by altering the distribution of the blood in the 
organs, although it is difficult to estimate how far the improvement is 
due to the remedy and how far it is spontaneous. In order to produce 
any marked effect on internal organs, the more powerful irritants must 
be used, such as mustard or cantharides. It is not necessary, however, 
to produce actual vesication in the great majority of cases. Formerly 
blisters were opened and fresh irritants applied on the raw surface in 
order to prolong the effects, but this treatment was extremely painful, 
besides being liable to set up suppuration and ulceration, and it is 
very questionable whether any equivalent benefit followed. 

Counter-irritation must be applied only with the greatest caution in 
weak, badly nourished, or very old persons, as it may cause sloughing. 
In diabetes, the tendency to gangrene contraindicates blistering, and 
in very young children only mild irritants are used. 

Bibliography. 

Naumann. Vierteljahrsch. f. prakt. Heilkunde, lxxvii., p. 1, and xciii., p. 133. 

ZiHsser. Deutsche Klinik., 1865, p. 127. 

Rohrig. Ibid., 1873, p. 209. 

Rohrig and Zuntz. Pfliiger's Arch., iv., p. 57. 

Paalzow. Ibid., iv., p. 492. 

Wertheimer. Arch, de Phys., 1894, pp. 308 and 724. 

Heidenhain. Pfliiger's Arch., iii., p. 504; v., p. 77. 

Riegel. Ibid., iv., p. 350. 

Mantegazza. Schmidt's Jahrb., cxxxiii., p. 153. 

Jacobson. Virchow's Arch., lxvii., p. 166. 

Head. Brain, xvi., p. 1 ; xvii., p. 339. 

Schutler. Berl. klin. Woch., 1874, p. 294. 

Winternitz. Arch. f. exp. Path, und Pharm., xxxv., p. 77; xxxvi., p. 212. 

Roger. Arch, de Phys. [v.] v., p. 17. 

Samuel. Virchow's Arch., cxxvii., p. 467. 

Hay. Saline-Cathartics, pp. 128-144. 

Buchner, Fuchs, Megele. Arch. f. Hygiene, xl.. p. 347. 

Wechsberg. Ztschr. f. klin. Med., xxxvii., p. 360. 

An enormous number of drugs produce irritation of the skin, and 
it would be idle to attempt to enumerate them hero. In many in- 
stances, however, the irritant action is insignificant in comparison with 
the other effects produced, and these will, therefore, ho discussed else- 
where; among these are found some of the alkaloids, the acids and 
alkalies, and many other inorganic preparations. Irritation of the -km 



86 ORGANIC SUBSTANCES ACTING LOCALLY. 

may also be produced by heat and cold, and in fact burning in various 
forms was formerly used as a means of counter-irritation. Heat is 
still employed to cause irritation of the skin and subcutaneous tissues, 
and to promote their circulation. Thus, poultices and hot water com- 
presses are beneficial in many local inflammations, though the same 
effects may generally be obtained by the use of the milder irritants. 
The effect of cold on the skin is more frequently demonstrated by 
bathing, and will be touched on in relation to the antipyrine series. 

Apart from those drugs in which the irritation of the skin is merely 
an incident in a wider general action, there are a number of prepara- 
tions which are used almost exclusively for this purpose. They may 
be divided into three classes: the volatile irritants, such as turpentine 
oil; the mustard series, some of which are also volatile; and those 
which are either non-volatile or only boil at high temperatures, such 
as cantharidin. 

I. The Turpentine Oil Group. 

Under the volatile irritants may be included a large number of the 
ethereal oils and many members of the methane and of the aromatic 
series; but among the ethereal oils those which possess a low boiling 
point, that is, those which contain a large proportion of terpene, with 
comparatively little oxygen, are found to possess a more penetrating 
action than the others. At the same time, the taste and odor of these 
oils is often less pleasant than that of the others, so that they are less 
used as flavors and carminatives. The oils derived from the Coni- 
ferae have, for this reason, been more largely used than the others for 
their effect on the skin, although several other volatile preparations are 
recognized by the pharmacopoeia for this purpose. The action of these 
oils is similar in other respects to that of the general group (see p. 61), 
so that it need not be discussed here. 

Preparations. 

Terebinthina, turpentine (IT. S. P.), Thus Americanum, Frankincense 
(B. P.), a concrete oleoresin obtained from Pinus palustris and other species 
of Pinus. 

Terebinthina Canadensis (U. S. P., B. P.), Canada balsam, a liquid oleo- 
resin obtained from Abies balsamea. 

Pix Burgundica, Burgundy Pitch (U. S. P., B. P.), an oleoresin derived 
from Abies excelsa, Norway spruce fir, contains less volatile oil than turpen- 
tine. 

Oleum Terebinthina (U. S. P., B. P.), oil of turpentine, a volatile oil 
distilled from turpentine, 0.1-0.5 c.c. (2-8 mins.) ; as an anthelmintic, 8-15 
c.c. (2-4 fl. drs.). 

Oleum Terebinthinse Rectification (U. S. P.) is formed from ordinary oil of 
turpentine by redistillation with lime water, in order to remove any acids 
and resin which may be contained in it. It consists of a mixture of terpenes 
(C 10 H 16 ). After long standing it undergoes partial oxidation among other 
changes, and contains some oxidizing substance which was formerly sup- 
posed to be ozone. 

IAnimentum Terebinthinee (U. S. P., B. P.). 

IAnimentum Terebinthinse Aceticum (B. P.) is formed by mixing turpentine, 
glacial acetic acid and camphor liniment. 






SKIN IRRITANTS AND COUNTER-IRRITATION. 87 

Emplastrum Picis Burgundicse (U. S. P.). 

Emplastrum Picis (B. P.), pitch plaster. 

Oleum Pini (B. P.), the oil distilled from the fresh leaves of Pinus'pumilis 

Terebenum (U. S. P., B. P.), a liquid formed from oil of turpentine by the 
action of sulphuric acid. It consists of a number of terpenes, one of which 
is the pure substance known as terebene. Its odor is more pleasant than 
that of turpentine oil, which it closely resembles in most other points. It 
does not cause any rotation of a ray of polarized light. 

Terpini Hydras (U. S. P.), terpin hydrate, is a crystalline Bubstance 
( C io H i 6 ( OH: )2 + H 2°) derived from oil of turpentine by the action of nitric 
acid in the presence of alcohol and water. It possesses almost no odor, is 
insoluble in water, and melts at about 116° C. 

Sabina (U. S. P.), the tops of Juniperus sabina, savine, contains as its ac- 
tive principle 01. Sabinae, a volatile oil which resembles that of turpentine 
in many respects, but is not identical with it. 

Oleum Juniperi (U. S. P., B. P.), oil of Juniper, is derived from the juni- 
per berries and consists mainly of terpenes. Dose, 0.03-0.2 c.c. (£-3 mins.). 

Spiritus Juniperi (U. S. P., B. P.), 1-4 c.c. (15-60 mins.). 

Spiritus Juniperi Compositus (U. S. P.), 4-8 c.c. (1-2 fl. drs.). 

In addition to these preparations the following may be mentioned here as 
possessing similar action and uses. 

Linimentum Chloroformi (U. S. P., B. P.). 

Linimentum Camphorse (U. S. P., B. P.). 

Linimentum Camphorse Ammoniatum (B. P.). 

Linimentum Saponis (U. S. P., B. P.), very slightly irritant. 

Emplastrum Arnicse (TJ. S. P.). 

Ceratum Camphorse (TJ. S. P.). 

Therapeutic Uses. — Turpentine oil is used externally as a rubefacient, 
and differs from mustard and cantharidin in its greater penetrating 
power. It is not so irritant, however; it blisters only after long appli- 
cation, and the vesication produced is very painful and heals slowly, 
from the vapor penetrating into the deeper tissues. It is, therefore, 
employed to produce rubefaction only, and ought to be removed when 
this is attained. For this purpose any of the liniments of the group 
may be employed, or a more intense action may be got from the " tur- 
pentine stupe," which is made by dipping flannel in hot water, wringing 
it dry, and then dropping warm turpentine oil on it.' Turpentine 
preparations are used especially in rheumatic affections of the joints or 
muscles, and in sciatica. The oleoresins may be formed into ointments, 
or plasters, and used as feeble stimulants in skin diseases. Turpen- 
tine oil is a fairly strong antiseptic, and is less irritant than many of 
the more powerful ones. It is often inhaled in lung diseases such as 
tuberculosis or gangrene, and has the effect of lessening the odor in 
the latter; the oil may be simply allowed to evaporate, but is much 
more efficient when sprayed into the air. Many of the resorts for 
phthisical patients are stated to be rendered especially suitable for the 
treatment of this disease by the neighborhood of coniferous forests, 
which are supposed to dissipate the oils into the atmosphere ; but this 
is probably only an insignificant factor in the treatment. Turpentine 

Alcohol has recently been applied in a similar way in phlegmon and other forms of 
inflammation. Gauze is soaked in alcohol (60-96 per cent. ), wrong out. wound round 
the affected part and covered with cotton and oil-cloth. 



88 ORGANIC SUBSTANCES ACTING LOCALLY. 

oil is occasionally added to baths in order to cause a slight general 
stimulation of the skin, which may be of benefit in some skin diseases 
and also in general debility under certain conditions; and pine-needle 
baths have some reputation in Germany for the same reason, the water 
being supposed to extract the oil. 

Internally, turpentine oil is occasionally employed as a vermifuge, 
but is inferior to other preparations used for this purpose. A few drops 
are often added to purgative enemata to increase their efficiency. It has 
been given by the mouth in order to lessen flatulence and to disinfect 
the intestine in various diseases, among others, typhoid fever, although 
its value here is disputed. Preparations of turpentine oil and juniper 
are reliable and fairly powerful diuretics, but must not be prescribed 
in irritation of the kidney. The turpentine preparations h a ve a cer- 
tain reputation as expectorants, and terebene has been especially ad- 
vised for this purpose ; they are also given internally as pulmonary 
disinfectants. In some forms of neuralgia their internal administration 
has been found beneficial, and oil of turpentine has been used in 
internal hemorrhage, but with doubtful results. 

Oil of turpentine was formerly believed to form ozone when it had 
been long exposed to the air, and old oil of turpentine was therefore 
recommended in cases of phosphorus poisoning, as it was supposed 
that it would oxidize the phosphorus in the stomach and thus render 
it innocuous. Recent investigators have, however, failed to detect 
ozone or peroxide of hydrogen in turpentine, and have not been able 
to confirm the older statements regarding its efficacy in phosphorus 
poisoning. 

Bibliography. (See page 72.) 

Along with these may be mentioned a series of resins which have some 
slight irritating effect on the skin, and have been used in the treatment of 
skin diseases. 

Resina (U. S. P., B. P.), resin, colophony, is the residue left after distill- 
ing off the volatile oil from turpentine. 

Ceratum Resinse (U. S. P.). 

Emplastrum Resinse (U. S. P., B. P.), adhesive plaster. 

Unguentum Resinse (B. P.). 

Galbanum (B. P.), a gumresin obtained from Ferula galbaniflua and 
probably from other species. It contains some volatile oil, gums and resin. 
Dose, 5-15 grs. 

Pilula Galbani Composita (see Asafoetida). 

Ammoniacum (U. S. P., B. P.), a gumresin obtained from Dorema Am- 
moniacum, and containing a small quantity of a volatile oil with an unpleas- 
ant odor. 

Emplastrum Ammoniaci et Hydrargyri (U. S. P., B. P.). 

Emulsum Ammoniaci (U. S. P.), 15-30 c.c. (|— 1 fl. oz.). 

Mistura Ammoniaci (B. P.), \-l fl. oz. 

Guaiaci Lignum (U. S. P., B. P.), the heart- wood of Guaiacum officinale. 

Guaiaci Resina (U. S. P., B. P.), the resin obtained from Guaiacum offici- 
nale, contains several resinous acids, some volatile oil and gums. It is col- 
ored deep blue by oxidizing agents. 

Tinctura Guaiaci (U. S. P.), 4 c.c. (1 fl. dr.). 

Tinctura Guaiaci Ammoniata (U. S. P., B. P.), 2-4 c.c. (l-l fl. dr.). 

Mistura Guaiaci (B. P.), \-l fl. oz. 



SKIN IRRITANTS AND COUNTER-IRRITATION. 89 

Trochiscus Guaiaci Resinse (B. P.), each containing 3 grs. 

Elemi resin (not official) is obtained from a number of trees of the order 
Burseracese, and contains volatile oil and resins. 

Unguentum Elemi (not official). 

Myrrha (U. S. P., B. P.), a gumresin obtained from Commiphora Myrrha 
(U. S. P.), from Balsamodendron Myrrha (B. P.), containing a small quantity 
of volatile oil. 

Tinctura Myrrhse (U. S. P., B. P.), 2-4 c.c. (i-l fl. dr.). 

Pilules Aloes et Myrrhse (U. S. P., B. P.). 

Tinctura Aloes et Myrrhse (U. S. P.). 

Mistura Ferri Composita (U. S. P.). 

Many other resins have been used in therapeutics, but have been aban- 
doned, a fate by which these survivors seem to be threatened. They are 
occasionally used externally as mild irritant applications in skin affections. 
Galbanum, Ammoniacum, Guaiacum and Myrrh have been used internally 
for many different purposes, as expectorants, diaphoretics, diuretics, aperi- 
ents, and have enjoyed a reputation in the treatment of amenorrhcea. They 
may be used to suspend insoluble bodies, as the gum contained causes them 
to form emulsions when water is added. 

II. Mustard. 

Mustard occurs in two forms in the pharmacopoeias, Black Mustard, 
Sinapis nigra, and White Mustard, Sinapis alba. Black Mustard con- 
tains a glucoside, Potassium Myronate or Sinigrin, and a ferment, 
Myrosin, which decomposes it in the presence of water into dextrose, 
potassium bisulphate and allyl-isosulphocyanate or volatile oil of 
mustard. 

Sinigrin. Volatile oil, 

C 10 H 18 KNS 2 O 10 = CSNC 3 H 5 + C 6 H 12 6 + KHSO, 

Volatile oil of mustard is formed in various other Cruciferae when they are 
mixed with water. Thus horseradish root (Armoracia, B. P.) contains it, 
while the allied species Cochlearia officinalis apparently contains the corre- 
sponding isobutyl compound. Garlic (Allium, U. S. P.) is also believed to 
contain a small quantity of mustard oil, although this is disputed ; in any 
case, the amount is too small to induce much irritation, although garlic 
poultices are sometimes employed in domestic medicine. 

White mustard contains another glucoside, Slnalbin, which is also 
decomposed by the Myrosin in the presence of water. The products 
are entirely different, however, dextrose, sulphate of sinapine (an alka- 
loid), and an oil of mustard containing an aromatic nucleus being 
formed. 

Sinalbin. Oil of Mustard. Sinapine Sulphate. 

C 30 H 44 N 2 S 2 O 16 = C (i H 4 (OH)CH 2 NCS + C 16 H 23 N0 6 H a S0 4 + C 6 H 12 6 

The oil of white mustard differs from that of the black in being Less 
irritant, and in being destroyed by heat. 

Action. — Either of these oils is intensely irritant when applied to 
the skin, and if left long enough produces blistering, which is more 
painful than that caused by cantharides, and is said to heal less readily. 
This is probably due to the oils penetrating more deeply into the tissues, 
and thus setting up more extensive inflammation. Mustard is accord- 



90 ORGANIC SUBSTANCES ACTING LOCALLY. 

ingly used only to induce rubefaction, and ought to be removed before 
actual vesication occurs. When the crude drug is moistened and ap- 
plied to the skin, the oil is formed only slowly, so that the longer it 
remains applied, the more intense is the action. The glucosides in 
themselves have little or no action, and the products of their decom- 
position are harmless, with the exception of the oils. 

Preparations. 

Sinapis Alba (U. S. P.), Sinapis Albse Semina (B. P.), the dried ripe seeds 
of Brassica alba. 

Sinapis Nigra (U. S. P.), Sinapis Nigrae Semina (B. P.), the dried ripe 
seeds of Brassica nigra. 

Sinapis (B. P.), a mixture of the powdered seeds. 

Charta Sinapis (U. S. P., B. P.), mustard powder rendered adhesive by 
India-rubber, applied to sheets of paper and dried. The U. S. P. prepara- 
tion is formed from the black mustard, the B. P. from a mixture of the two. 

Oleum Sinapis Volatile (U. S. P., B. P.), derived from black mustard. 

Linimentum Sinapis (B. P.), formed from volatile oil of mustard, camphor 
and castor oil. 

Linimentum Sinapis Compositum (U. S. P.), contains volatile oil of mustard, 
mezereum and camphor. 

Uses. — Mustard is largely used as a condiment and to promote 
appetite, but is never prescribed for this purpose. In large quantities 
it causes violent irritation of the stomach and bowel, with vomiting, 
purging, acute pain and tenderness in the abdomen, and collapse. 
Mustard and warm water is a convenient emetic in emergencies, as in 
cases of poisoning. 

The plaster or leaf (charta) is the form in which it is generally used 
in therapeutics. It contains the glucoside, which is slowly decomposed 
by the ferment when the plaster is dipped in warm water for a few min- 
utes before application. Another popular application is the mustard 
poultice, in which powdered mustard is sprinkled on an ordinary 
poultice. Mustard is also added to baths occasionally when slight 
irritation and consequent congestion is desired over a large surface. 
For this purpose 2—4 teaspoonfuls of the dry powder are added for 
each gallon of water. In preparations of mustard it is important to 
avoid a temperature of over 60° C. (140° F.), as the ferment is de- 
stroyed above this. The plaster is left on the skin only for 15 to 30 
minutes, when it is used as a rubefacient. 

Thiosinamine (CSNH 2 NHC 3 H 5 ) is formed from volatile oil of mustard by 
the action of ammonia and alcohol, and has been advised to remove the scar 
tissue left after lupus and extensive burns of the skin. It is applied as a 
plaster or injected dissolved in 2 parts of glycerine and 8 of water. The 
action has not been explained, but is said not to be due to inflammation. 



III. Cantharidin Series. 



• 



Another series of local irritants comprises non-volatile substances, 
of which cantharidin is the best known. It is the anhydride of can- 
tharidic acid, which does not exist itself, but the salts of which are 



SKIN IRRITANTS AND COUNTER-IRRITATION. 91 

formed from cantharidin by the action of bases. Cantharidin is rep- 
resented by C 10 H 12 O 4 , and is a derivative of benzol. Its action od 
the central nervous system resembles, it is stated, that of the other 
members of that series, but is of no importance in comparison with 
its local irritant effects. Cantharidin is found in Spanish fly (Can- 
tharis vesicatoria, or Lytta vesicatoria) and in several allied sped 
Coleoptera (beetles). 

Action. — The irritant action of cantharidin and of many other 
drugs was formerly supposed to be due to its being an anhydride, 
but other anhydrides have no such specific action, and the canthari- 
dates are quite as powerful as cantharidin. 

Animals vary very considerably in the degree in which they react 
to cantharidin, the most noted example being the hedgehog, which is 
capable of surviving a dose of the poison sufficient to poison an adult 
man. Fowls and rabbits also possess a high degree of congenital 
tolerance for this poison, although none of these is absolutely insus- 
ceptible to it. 

Applied to the shin, cantharidin produces redness, smarting and 
pain, followed very soon by small vesicles, which later coalesce into one 
large blister. This is much less painful than the vesication produced 
by mustard, because less of the irritant penetrates into the deeper tis- 
sues than in the case of the volatile mustard oil. If the blister be 
broken, however, and the unprotected dermis be allowed to come in 
contact with the irritant, violent inflammation with much pain, suppu- 
ration and even sloughing may follow. 

When large quantities of cantharidin are given internally, the same 
irritant action takes place along the alimentary tract. If taken in 
solution, blisters arise in the mouth and throat, and the pain and 
swelling in the oesophagus may be so acute as to prevent swallowing. 
The irritation of the stomach produces vomiting, followed by purging 
with excruciating pain in the abdomen, and all the symptoms of shock 
and collapse. 

Cantharidin is absorbed from the alimentary canal, and also to a less 
extent from the skin, but has no important action on the internal 
organs, with the exception of those by which it is eliminated. The 
heart is often accelerated in poisoning in animals, but has been slowed 
in some cases in man, while in others it was rapid and feeble. The 
respiration becomes rapid and dyspnceic some time before death, and 
some confusion, deepening into coma and convulsions, indicate a 
specific action on the central nervous system. Vomiting also occurs 
on subcutaneous injection, but the presence of ulceration of the stomach 
and of diarrhoea when it is absorbed from the skin, indicates that some 
of the poison is excreted into the alimentary tract, and the vomiting in 
these cases may therefore be of peripheral rather than of central origin. 
In the process of excretion, cantharidin has the same effects on the 
organs involved as on those of absorption. These effects are 
only in the genito-urinary tract in the vast majority oi' cases of ]>« Hom- 
ing. Comparatively small quantities irritate the bladder, and cause a 



•92 ORGANIC SUBSTANCES ACTING LOCALLY. 

constant desire to micturate, with pain in doing so. In somewhat 
larger amount it sets up an acute nephritis with albuminuria, pain in 
the kidney region, and sometimes blood in the urine. The inflam- 
mation of the bladder and urethra produces intense pain and often 
priapism ; in women abortion is said to occur occasionally, and in both 
sexes the irritation may lead to increased sexual desire. 

The irritation of the kidneys by small doses increases their secretion, 
and cantharides was therefore considered a diuretic formerly. The 
tendency to produce nephritis renders it a dangerous internal remedy, 
however, and its diuretic power is quite insignificant in comparison 
with that of caffeine. 

Preparations. 

Cantharis (U. S. P., B. P.), Spanish Fly, the dried beetle, Cantharis vesi- 
catoria. 

Ceratum Cantharidis (U. S. P.). 

Collodium Cantharidatum (U. S. P.). 

Tinctura Cantharidis (U. S. P., B. P.), 0.1-0.3 c.c. (2-5 mins.). 

Emplastrum Picis Cantharidatum (U. S. P.), formed by the mixture 
of the cerate with Burgundy pitch. It is much less irritant than the cerate, 
but sometimes produces blistering, if applied for a long time. 

Emplastrum Cantharidis (B. P.). 

Emplastrum Calefaciens (B. P.), warming plaster. 

Acetum Cantharidis (B. P.). 

Unguentum Cantharidis (B. P.). 

Collodium Vesicans (B. P.). 

Liquor Epispasticus (B. P.). 

Therapeutic Uses. — Cantharides is at present used almost exclusively 
as a skin irritant, and more particularly as a vesicant. In the United 
States the cerate is generally used for this purpose, and is applied to 
the skin by means of adhesive plaster; the corresponding preparation 
of the B. P. is the cantharides plaster. It is to be noted that, in order 
to produce actual blistering, the plaster has to remain in contact with 
the skin some 8—10 hours, but an equal effect may be achieved by re- 
placing the plaster by a hot poultice after 4-6 hours, when the skin 
irritation has reached the stage of redness. Cantharides is also used to 
cause rubefaction and commencing vesication (flying blister) ; this may 
be done by the use of these preparations, or by means of the canthari- 
dated pitch plaster, U. S. P., or the warming plaster, B. P. Blister- 
ing collodion is used rarely in unmanageable cases, in which there is 
a risk of the plaster being removed by the patient. The ointment is 
said to induce blistering sooner than the plaster. 

Cantharidin is liable to be absorbed from the skin, and its applica- 
tion is therefore avoided where there is any tendency to renal inflam- 
mation. 

Cantharides has been used not infrequently as an aphrodisiac, and 
several cases of poisoning have occurred from its administration for this 
purpose. In cattle it is largely employed to this end in some coun- 
tries, and in man it has undoubtedly similar effects in some cases 
through the irritation of the bladder and urethra, but its use for this 



SKIN IRRITANTS AND COUNTER-IRRITATION. 93 

purpose is always liable to produce nephritis. As an emmenagogue, 
cantharides has a certain popular reputation, which however has been 
shown to be unmerited, any influence which it may possess on the 
menstrual flow being quite insignificant, and probably due only to the 
irritation of the bladder and urethra. 

Cantharides has been advised internally in some forms of renal and vesical 
disease, but it is an exceedingly dangerous remedy in these conditions. In 
1891, Liebreich proposed the treatment of tuberculous affections with can- 
tharidinates, in the belief that these would cause an inflammatory reaction 
around the diseased nodules, and would thus lead to their bemg destroyed 
or encapsuled in cicatricial tissue. It has not been determined whether 
cantharidin acts more powerfully on irritated tissues, such as those around 
the tubercles, but experience has shown that no benefit followed Liebreich's 
treatment, while in several cases severe nephritis resulted from the injection, 
and the method has therefore fallen into disuse. 

Cantharides is sometimes a constituent of hair washes, its irritant action 
on the skin being credited with causing a more rapid growth of the hair. 

In cases of Poisoning with cantharides, the stomach ought to be 
emptied as rapidly as possible by the stomach tube, provided the 
oesophagus allows of its passage. Demulcents and albuminous su In- 
stances are of use in slowing the absorption, but all oily or fatty 
bodies must be avoided, as they tend to dissolve the cantharidin and 
thus promote its absorption. Opium may be given for the pain, and 
if collapse sets in, the ordinary measures must be taken to combat it. 

Poison Ivy and Poison Oak. — The commonest form of poisoning in 
the United States is the skin eruption produced by the leaves of poison 
ivy and poison oak (Rhus toxicodendron and venenata) which Pfaff 
has recently shown to be due to the presence of a neutral body, Toxi- 
codendrol, resembling closely the other members of this group. The 
effects of poison ivy can arise only from touching the plant, the poison- 
bus principle not being volatile. Very minute quantities of toxico- 
dendrol are sufficient to produce skin eruptions, however, -yo 1 ,,,, mg. 
causing distinct symptoms in susceptible persons. The popular belief 
that skin affections can be induced by approaching the plant, without 
actually touching it, is probably accounted for by the facts that the 
eruption may be very late in making its appearance, and that poison 
ivy is very frequently mistaken for harmless climbing plants. 

In the dermatitis from poison ivy, Pfaff recommends that the skin 
be washed and scrubbed with soap and water, or with alcohol, or a 
solution of lead acetate in alcohol. Ointments and oily liniments are to 
be avoided, as they dissolve the toxicodendrol and tend to spread ii 
over the skin and thus produce further inflammation. For the same 
reason, the alcohol used to wash the part must be removed entirely, as 
the poisonous principle is soluble in it, while insoluble in water. 

Several little known substances may be classed along with cantharidin, 
which they resemble in their violently irritating effects on the skin and 
mucous membranes, and in being non-volatile. They are of little impor- 
tance in therapeutics, but not infrequently give rise to accidental poisoning. 



94 ORGANIC SUBSTANCES ACTING LOCALLY. 

A number of the Ranunculacese order are irritants, and this has been be- 
lieved to be due to their containing Anemonin, C 10 H 8 O 4 , which is closely con- 
nected to cantharidin in its chemical structure, but this has been disputed 
recently by Brondgeest, who asserts that this body is a convulsive poison. 
Noel and Lambert also state that anemonin is not the irritant contained in 
Anemone Pulsatilla, which owes its irritant effects to some other more 
poisonous constituent. In Mezereum, Buchheim found an anhydride which 
he termed Mezerein, but Springenfeldt states that the action is due to an oil 
and to the acid which it contains, which resemble croton oil and crotonoleic 
acid in their effects. Cardol, found in the fruits of Anacardium occidentale 
and in Seraecarpus anacardium, is a very powerful irritant, and has been used 
to a limited extent as a vesicant. Cardol is probably a mixture of a number 
of substances, but it is unknown to which of these it owes its activity. 
Euphorbin is said by Buchheim to be the irritant principle in the Euphorbia 
resin (Euphorbia resinifera, etc.), and to resemble cantharidin in its anhy- 
dride form, but the salts and the euphorbic acid which is formed from them 
by acids are inactive, while the salts of cantharidic acid are irritant, and 
cantharidin is reformed when they are broken up by acids. A very 
poisonous member of the Euphorbiacese is the Manicheel tree, growing in 
the West Indies, and it apparently belongs to this series. 

Capsicum contains one or more non volatile irritant substances which 
probably resemble the principles of this series more closely than any other. 
Capsicum is used in small quantities internally and has therefore been men- 
tioned along with the pepper series, but it is also used occasionally as a skin 
irritant. Pepper is also used as a rubefacient in domestic medicine. 

Chaulmoogra Oil, obtained from Gynocardia odorata, is apparently similar 
in character to the members of this group, although it is less irritant. It 
is used externally as an application to bruises, and both externally and 
internally in leprosy, although it is probably of little avail in this disease. 
]t is said to owe its activity to Grjnocardic acid, which it contains in combi- 
nation with glycerin. Croton oil is also used as a skin irritant, but will be 
treated of in connection with the purgatives (page 99). 

Many other plants possess irritant, poisonous properties, which would ap- 
parently entitle them to a place in this series, but so little is known of their 
active principles and of their effects, that they may be omitted for the present. 

Preparations. 

Mezereum (TJ. S. P.), Mezerei Cortex (B. P.), the bark of Daphne meze- 
reum and of other species. 

Extractum Mezerei Fluidum (U. S. P.). 

Mezereum is also contained in several of the sarsaparilla preparations 
(U. B. P.). 

Rhus Toxicodendron, poison ivy, the fresh leaves of Rhus radicans 
(IT. S. P.). 

Capsicum (U. S. P , B. P.). 

Emp'astrum Capsici (U. S. P.). 

Unguentum Capsici (B. P.). 

(For the other preparations of Capsicum see page 73.) 

Pulsatilla (U. S. P.), the herb Anemone Pulsatilla and A. pratensis. 

Bibliography. 

Radecki. Inaug. Diss., Dorpat, 1866. 

Aufrecht. Centralbl. f. med. Wissensch., 1882, pp. 545, 849. 

Eliaschoff. Virchow's Arch., xciv., p. 323. 

Liebreich. Therap. Monatsheft, 1891, p. 169 ; 1892, p. 294 ; 1895, p. 167. 

Buchheim. Arch. d. Heilkunde, xiii., p. 1. 

Comil. Coraptes rendus de l'acad., civ., p. 1875. 

Lewm. Deutsch. med. Woch., 1901, p. 184. 







VEGETABLE PURGATIVES. 95 

Pfaff. Journ. of Exp. Med., ii., p. 181. (Toxicodendrol. ) 
Springenfeldt. Inaug. Dis., Dorpat, 1890. (Mezereum. ) 
Brondgeest. Schmidt's Jahrbuch, ccxx., p. 131. (Anemonin. ) 
Noel and Lambert. Arch, de Pharmacodynamique, iv., p. 169. (Pulsatilla and 
anemonin. ) 

VII. VEGETABLE PURGATIVES. 

Purgatives are drugs which are employed in medicine to evacuate 
the bowel of its contents. Many drugs produce evacuation in the 
course of their action, but have other effects of importance and are not 
included in this class. Thus the members of the preceding classes of 
skin irritants induce diarrhoea, but this is accompanied by irritation of 
the mouth, throat and stomach, and in many other forms of poisoning, 
diarrhoea is a prominent feature, but is accompanied by vomiting or 
some other symptom. The ideal purgative is devoid of any effects 
whatsoever, save in the intestine ; it passes through the stomach with- 
out materially deranging its function, and is not absorbed, or at any 
rate is absorbed so slowly that it has time to unfold its action through- 
out the intestine. The vegetable purgatives act through their irritant 
properties, which in some instances are elicited only by the action of 
the secretion of the intestines and of the neighboring glands. Thus 
some of the purgatives pass through the stomach in the form of bland, 
non-irritant compounds (castor oil), which are broken up by the diges- 
tive processes in the intestine, while others perhaps owe their activity 
in the intestine to their solution or suspension in the juices. 

Many classifications of the purgatives have been based on their 
effects, and some of the terms are still retained, such as aperient, ecco- 
protic, laxative, purgative, cholagogue, hydragogue, cathartic or drastic. 
But the effect of the purgatives is determined largely by the dose and 
by the condition of the intestine, so that a small dose may act as an ape- 
rient, laxative or eccoprotic, while a larger quantity of the same drug, 
or even the same dose in a more susceptible individual, may act as a 
drastic or hydragogue cathartic. It is, therefore, preferable to classify 
them according to their chemical nature as far as that is known, and 
in this way three classes may be formed, (1) purgative oils, (2) purga- 
tives of the anthracene series, (3) the jalapin and colocynthin group. 

Symptoms. — In moderate doses the purgatives simply hasten the 
normal movements of the intestines, and the stool is of the ordinary ap- 
pearance and consistency (laxative, aperient, or eccoprotic action). In 
larger quantities they cause a more profuse evacuation than normally, 
and the stools, which are repeated at short intervals, are of a looser, 
more fluid consistency. Their action is accompanied by considerable 
pain and colic, and the hurried movements of the intestine are shown 
by the characteristic gurgling sounds. Large quantities of the more 
powerful purgatives may cause all the symptoms of acute enteritis; 
the stools at first contain the ordinary faecal substances accompanied 
by more fluid than usual, but later consists largely of blood-stained 
mucous fluid with little or no resemblance to ordinary i-eces. This 
violent purgation, which is not induced in therapeutics, is accompanied 



96 ORGANIC SUBSTANCES ACTING LOCALLY. 

by pain and tenderness in the abdomen, and may induce shock, col- 
lapse and eventually death. 

Action. — The origin of the fluid of the stools after purgatives has 
been much debated. According to many authors, they accelerate the 
passage of the intestinal contents so much that there is no time for 
the absorption of the fluid, and the fseces escape in the fluid con- 
dition in which they normally exist in the small intestine. Other in- 
vestigators hold that purgatives cause fluid to pass into the intestine, 
either by increasing the normal secretions, or by causing an inflam- 
matory exudate from the vessels. Both parties have founded, or at- 
tempted to confirm their statements by the results of the injection of 
the purgatives into loops of intestine isolated from the rest of the 
bowel. In these, some observers (Brunton, Boy) have found a larger 
accumulation of fluid after the injection of the purgatives, while 
others (Thiry, Badziejewski) found no more fluid after purgatives than 
after indifferent fluids. These contradictory results are probably due 
to the methods adopted, and the quantity of the drug injected. In 
small quantities, such as are used in the vast majority of cases in ther- 
apeutics, the irritation produced by the purgatives is probably only 
enough to accelerate peristalsis somewhat, and the fluid of the stools 
is drawn partly from the food and partly from the ordinary secretions 
of the digestive organs. In these cases the intestine is not actually 
inflamed, although some congestion may occur in it, as in all organs 
in a state of abnormal activity. On the other hand, when large quan- 
tities are ingested a true inflammation of the intestine occurs, mani- 
fested by increased movement, congestion, the exudation of fluid into 
the lumen of the bowel, and pain. In these cases the intestine pre- 
sents the usual signs of inflammation ; it is red and congested, and 
contains a muco-purulent fluid and often blood. The matter, therefore 
resolves itself into a question of dose ; if it be small, the fluid is not 
an exudate, if it be large the fluid is partly an inflammatory product. 
No very distinct difference exists between the stools produced by pur- 
gatives and the normal faeces except in the larger proportion of water 
and of sodium. The excess of the latter has been explained by some 
as due to the exudation of serum, by others as the effect of the rapid 
evacuation, which prevents the normal absorption of the bile, pan- 
creatic and intestinal secretions. 

The colic produced by purgatives is not due to the inflammation of 
the intestinal wall, but is probably explained by the more vigorous 
contractions of the walls of the bowel and the difficulty in forcing on 
hard fsecal masses in the large intestine. The tenderness produced 
by large quantities of the purgatives, on the other hand, would seem 
to indicate inflammation. 

A further question is whether a purgative must come in contact 
with the whole bowel, or whether irritation set up at one particular 
spot does not cause peristaltic waves through the whole intestine and 
induce evacuation. Badziejewski maintains that purgation may be ef- 
fected by drugs in the stomach without their entering the bowel at all, 



VEGETABLE PURGATIVES. 97 

and supposes that this is a reflex action. This view would be in 
accord with the statements of Traube and Wood, that division of 
the vagi hinders or entirely prevents the action of some purgatives, 
and, on the other hand, with the fact that the bowels may be emptied 
by enemata, which are too small to reach the colon. Radziejewski's 
results, however, might be explained by the drugs in his experiments 
having been absorbed in the stomach, and afterwards excreted in the 
intestine, and thus producing irritation, while Traube and Wood's ex- 
periments require confirmation, as the action of purgatives on animals is 
often very variable. The drug given by enema may be absorbed from 
the rectum and excreted in the upper part of the intestine, although 
this is improbable. On the other hand, Hess found that when the 
bowel was occluded by an india-rubber ball, purgatives applied above 
the ball failed to induce evacuation of the bowel, and he therefore 
concludes that they produce purgation only when they are brought in 
contact with the large intestine, and that irritation of one part cannot 
induce activity of another by either nervous or muscular conduction. 
This would seem to be confirmed in cases of artificial anus, in which 
purges given by the mouth have no effect upon that part of the bowel 
lying between the natural and the artificial opening. The question 
cannot be said to be decided, and requires further investigation, al- 
though the probability seems great that the purgatives cause evacu- 
ation only when they come into direct contact with a large part or the 
whole of the intestinal wall. 

Purgatives given by the mouth accelerate the movements of both the 
small and large intestine. In constipation, however, there seems no 
reason to suppose that the food is retarded in its passage through the 
small bowel. The delay takes place in the colon, and it is in remov- 
ing the sluggishness of the latter that purgatives are beneficial. 

The action of the purgatives is generally considered purely local, 
and strictly analogous to that of the skin-irritants. The irritation of 
the epithelium and of the nerve ends leads to increased activity of the 
deeper layers, which manifests itself in the bowel by contraction of 
the muscle, in the skin by vesication. But some of the purgatives 
seem to have a further action, which is of a more specific nature. 
Thus senna, aloin, frangulin, and colocynthin cause evacuation of the 
bowel when injected subcutaneously or into the blood, podophyllum 
resin causes violent purging and vomiting when thus administered, and 
croton oil has long been rubbed on the skin in order to relieve con- 
stipation, and is found to cause intestinal inflammation and purging 
when injected intravenously. It has accordingly been suggested that 
these have a specific action on the bowel quite apart from their irri- 
tant effects ; but it is quite possible that their intestinal effects are here 
due to their excretion into the bowel, which has been shown to occur 
in several instances. Other irritants applied subcutaneously or intra- 
venously often produce similar effects on the alimentary canal. 

The interval which elapses between the administration of a purga- 
tive and its effects varies with the dose, and also with the individual 
7 



98 ORGANIC SUBSTANCES ACTING LOCALLY. 

drug. In ordinary therapeutic doses, evacuation of the bowels occurs 
in most cases in 5-10 hours, but if large quantities of the more pow- 
erful purges, such as jalap or croton oil, be given, the effects may be 
elicited in two hours. Aloes and podophyllum differ from the others 
in the length of the interval, catharsis rarely or never occurring ear- 
lier than 10—12 hours after their administration, and often only after 
20-24 hours. 

The movement of the intestine induced by purgatives is accom- 
panied by an increase in the leucocytes of the blood similar to that 
observed in other forms of intestinal activity, e. (/., during digestion. 

The effects of the purgatives vary greatly in different animals. 
Thus, the rabbit is very refractory to most of the series, and often is 
killed by intestinal irritation without any evacuation being produced. 
The frog is unaffected by quantities which would produce poisoning in 
man, while the dog and cat respond much more readily. 

It was formerly supposed that purgatives increased the secretion of 
bile, and certain of them, which were believed to have a special activity 
in this direction, were known as Cholagogues. It has been shown of 
recent years that none of them possesses any action on the secretion of 
bile, although they may increase its excretion by hurrying it through 
the intestine and preventing its reabsorption. On the other hand, the 
presence of bile in the intestine is a condition necessary to the activity 
of many of the purgatives. Thus Buchheim and Stadelmann found 
that in the absence of bile the following purgatives are either quite in- 
active or very much less powerful than usual — podophyllin and podo- 
phyllotoxin, resin of jalap, convolvulin, resin of scammony, rhubarb, 
cathartic acid, and the sodium salt of gambogic acid. This is prob- 
ably due to some solvent action of the bile, for Stadelmann found that 
when soaps were given with some of these drugs their activity returned, 
and in other cases a comparatively slight modification of their chemical 
form was sufficient to restore their activity, even in the absence of 
either bile or soap. Analogous results have been observed from other 
causes than the absence of bile ; thus some of the pure principles of 
the purgatives are much less active than the crude drugs because the 
impurities of the latter alter their solubility. This alteration of the 
solubility may act in two ways : if the principle is rendered too soluble, 
it may be absorbed in the stomach and upper part of the bowel, and 
therefore fail to produce purgation ; on the other hand, it may be 
rendered so insoluble that it fails to come into intimate contact with 
the bowel wall, and therefore does not irritate it. The effects of such 
colloid substances as the bile and the gums of gamboge would be to 
delay the absorption of soluble substances in the upper part of the 
bowel, and at the same time to keep the insoluble resins in suspension. 

Few of the purgatives have any appreciable action after absorption, 
but general effects may be produced indirectly from their intestinal 
action. It is probable that reflexes are elicited by irritation of the 
bowel analogous to those discussed under skin irritants, but in addition, 
the congestion of the bowel produced by its activity must alter con- 



VEGETABLE PURGATIVES. 99 

siderably the distribution of the blood in the body. The belief in the 
efficacy of a purge in congestion of the brain may thus be based on a 
true " revulsive " action ; for the dilation of the intestinal vessels must 
necessarily lessen the blood pressure and thereby the blood supply to 
the brain. The congestion of the intestine is accompanied by a similar 
condition in the other pelvic organs, and the purgatives therefore often 
cause congestion of the uterus, with excessive menstrual flow, or in the 
case of pregnant women, abortion. Lastly, a certain amount of fluid 
is withdrawn which would otherwise be excreted by the urine, which 
is found to be proportionately diminished in amount. 

1. The Purgative Oils. 

Two very important members of the purgative series are Castor oil 
(Oleum Ricini), aud Crohn oil (Oleum Tiglii or Crotonis). 1 Castor oil 
consists almost entirely of an oil which resembles olive oil in most re- 
spects, but on saponification forms ricinoleic acid instead of oleic acid. 
This acid (C 17 H 32 (OH)COOH) differs from the fatty acids obtained 
from ordinary oils in being unsaturated and in containing a hydroxyl 
group. Castor oil is itself a bland, non-irritating fluid, but on passing 
into the intestine is decomposed by the digestive juices, and the 
ricinoleates thus formed are irritant and cause purgation. When the 
oil is saponified, and the free acid given by the mouth, the effects 
are quite different from those of the oil, for the taste is acrid and un- 
pleasant, and discomfort, nausea and vomiting may follow its in- 
gestion from its irritant action on the stomach. The oil, on the other 
hand, has a bland, if unpleasant, taste, and produces no effects on 
the stomach. Several other esters of ricinoleic acid have been shown 
by Meyer to resemble the glycerin ester (castor oil) in their purgative 
effects. 

Croton oil is decomposed into glycerin and crotonoleic acid, of which 
little is known except that it is similar to ricinoleic acid from a chemical 
point of view. It differs from it in the fact that crotonoleic acid is a 
much more irritant body, and in that some acid is found free in the oil. 
This free acid renders croton oil irritant before it reaches the intestine, 
although the same process goes on here as in castor oil, and the croton 
oil therefore becomes more irritant than elsewhere. On the skin, and 
in the throat and stomach, croton oil exerts its irritant action, but these 
effects may be avoided while it continues to act as a purgative, if the 
free acid be removed. Croton oil then becomes bland and non-irritant, 
and can be distinguished from castor oil only by its more powerful pur- 
gative action. Castor oil is absorbed from the intestine and disappears 
in the tissues in the same way as an ordinary oil. Nothing is known 
with certainty of the fate of croton oil in the body, but it is not un- 
likely that it is excreted in part into the large intestine. J^oth croton 
oil and castor oil are borne in much larger quantities by animals than 

1 Another plant containing a purgative oil is the Jatropha curcas, which bears the 
Barbadoes nuts, or purging nuts. It is somewhat weaker in its action than croton oil, 
and is said to be oftea substituted for it in specimens of croton oil obtained from India. 



100 ORGANIC SUBSTANCES ACTING LOCALLY. 

by man, and not infrequently the former causes acute enteritis without 
purgation. 

Castor oil may be given in very large quantities without producing 
any symptoms, save those of a mild laxative. Croton oil, on the other 
hand, acts as an irritant poison in any save the smallest doses, pro- 
ducing vomiting and violent purging with bloody stools, collapse and 
death. Castor oil is occasionally used as an emollient to the skin, 
and has been employed as a solvent for application to the eye, while 
croton oil has already been mentioned among the skin irritants. The 
harmless nature of castor oil is shown by its use in China as an article 
of diet. 

It was formerly a matter of dispute whether croton oil causes the formation 
of pus when injected subcutaneously, or whether the presence of microbes is 
necessary, but it seems unquestionable now that croton oil alone is capable of 
producing this effect, provided that it contains free crotonoleic acid. The 
contradictory results obtained by observers may be explained by the fact 
that croton oil occasionally contains very little free acid, and that the 
mammalian tissues are unable to saponify the oil save in the presence of the 
intestinal ferments. In the frog these ferments are present in the tissues, or 
perhaps the latter are capable of breaking up the oil, for Hirschheydt found 
that the neutral oil caused inflammation and hemorrhages in various parts 
of the body. 

In the beans from which castor oil and croton oil are derived, toxalbumins 
are found, and these were at one time supposed to be the active principles 
of the oils. (See Ricin.) It has been shown, however, that the oils are en- 
tirely free from these poisons, and that their action is due solely to the acids 
of which they are glycerides. 

Preparations. 

Oleum Eicini (U. S. P., B. P.), a fixed oil expressed from the seed, or 
bean of Ricinus communis. Dose, 4-30 c.c. (1-8 fl. drs.). 

Mistura Olei Bicini (B. P.), made up with cinnamon and orange flower 
water by means of mucilage, 1-2 fl. oz. 

Oleum Tiglii (U. S P.), Oleum Crotonis (B. P.), a fixed oil expressed 
from the seed of Croton Tiglium. Dose, 0.02-0.05 c.c. Q-l m.). 

Castor oil is difficult to take owing to its unpleasant taste. It may be 
given alone, in an emulsion flavored with sugar and some volatile oil, in 
wine, spirits or glycerin, or in flexible capsules. 

Croton oil is often given in a pill made up with bread crumb, or a single 
drop may be given on a lump of sugar or in solution in castor oil. 

2. The Anthracene Purgatives. 

A number of purgatives, Rhubarb, Senna, Aloes and Frangula, ow r e 
their activity to the presence of irritant anthracene (C 14 H 10 ) compounds, 
only a few of which have been isolated. The chemical examination of 
these drugs is a matter of great difficulty, as they each contain several 
active principles which are very nearly related to each other, and 
some of w T hich are undoubtedly the products of the composition of 
more complex bodies. In addition, several of the pure substances 
have been found to be less certain in their purgative action than the 



VEGETABLE PURGATIVES. 101 

crude drugs, probably because the colloids in the latter aid in their 
solution. 

All those which have been completely isolated hitherto have proved to be 
derivatives of anthraquinone, 

CH CH CH CH CH CH 

C/\CA ACAC 



HC \/o\/o\> H HC \/c\/\/ C11 

CH CH CH CH CO CH 

Anthracene. Anthraquinone. 

and some of the oxyanthraqninones seem to be widely distributed. Thus all 
the members of the group contain Emodin or trioxymethylanthraquinone, 
(C u H 4 (CH 3 )(OH) 3 2 ), and rhubarb and serma contain Chrysophanic acid or 
dioxymethylanthraquinone, (C u H.(CH 3 )(OH) 2 2 ), while a nearly related 
body has been found in Frangula. It is still undecided whether the emodin 
found in different drugs is identical or merely isomeric, and the same may 
be said in regard to chrysophanic acid. In addition, a number of other an- 
thracene bodies occur in these purgatives, some of them combined with 
sugars to form glucosides, but little is known regarding them, and it seems 
likely that some may prove to be impure emodin. Acid glucosides have 
been found in rhubarb, senna (Cathartin or Cathartinic acid) and in cascara 
and frangula (Cathartin and Frangulin). In the different species of aloes 
several Atoms (Barbaloin from Barbadoes aloes, Socaloin from Socotrine aloes, 
etc.) have been isolated. 

Several of the pure principles have been used as purgatives, although 
they seem on the whole to be less certain in their effects than the crude 
drugs. Chrysophanic acid does not cause purgation, owing to its rapid 
absorption. Frangulin has given satisfactory results, and Cathartin has 
also been used experimentally, but is very liable to undergo decompo- 
sition. Aloin is less certain in its effects than aloes, and it seems to be 
indisputable that the crystalline aloin itself is inactive in the bowel, but 
is there changed under certain conditions to an amorphous compound 
which has irritant effects. This active substance can be prepared from 
aloin by boiling in water, and may be present in the amorphous resin left 
after the extraction of aloin. The purgative action of aloes is increased 
by the addition of small quantities of alkaline salts and of iron. The 
presence of bile in the intestine is necessary to elicit its full effects, 
and it is generally stated that enemata of aloes are inactive unless 
bile is injected with them, but Kohlstock found that the same results 
could be attained by dissolving aloin in glycerin. The latter pro- 
duces evacuation when injected alone as an enema, it is true, but he 
used smaller quantities of it than are necessary for purgation, so that 
the role played by the bile is probably the same as that of glycerin — 
a purely solvent one. 

The absorption of these bodies has not been satisfactorily determined 
in most cases. The urine is rendered yellow after rhubarb and senna, 
owing to the absorption and excretion of chrysophanic acid, but ii is 
questionable whether the more active principles pass into the urine in 
appreciable amounts. When aloin is injected subcutaneously or intra- 



102 ORGANIC SUBSTANCES ACTING LOCALLY. 

venously, it is excreted for the main part into the bowel, and there pro- 
duces irritation and catharsis. Cathartin and frangulin also act as 
purgatives when they are injected subcutaneously, probably because 
they are excreted into the bowel, although this has not as yet been 
investigated. The yellow pigment of the urine after rhubarb and 
senna becomes a purple red on the addition of alkalies l ; the milk and 
skin also are said to assume a yellowish tinge from the presence of 
chrysophanic acid. 

In the rabbit aloin seldom causes purgation, and is excreted by the 
kidney in considerable quantity, especially when injected hypoder- 
mically. In passing through this organ it causes marked irritation 
and epithelial necrosis, which often proves fatal in a few days. No 
irritation of the kidney occurs in man, the dog, or the cat after aloin. 

Rhubarb contains a considerable amount of tannic acid, which acts 
as an astringent and therefore tends to cause constipation after the 
evacuation of the bowels. It is not well tolerated in some cases, its 
administration being followed by nausea, headache and giddiness, more 
rarely by skin eruptions of different kinds. 

Prepakations. 

U. S. P. — Rheum, rhubarb, the root of Rheum officinale. 

Extractum Rhei, 0.3-0.6 G. (5-10 grs.). 

Extractum Rhei EYuidum, 1-2 c.c. (15-30 mius.). 

Pilule Rhei (each contains 0.2 G. of rhubarb), 1-5 pills. 

Pilule Rhei Composite (contain aloes, myrrh and oil of peppermint), 
1-5 pills. 

Pulvis Rhei Compositus (Gregory's Powder) contains magnesia and 
ginger. Dose, 1-4 G. (20-60 grs.). 

Tinctura Rhei, 4-16 c.c. (1-4 fl. drs.). 

Tinctura Rhei Aromatica (contains several volatile oils), 2-8 c.c. Q-2 fl. drs.). 

Tinctura Rhei Dulcis (contains volatile oils and liquorice), 4-16 c.c. 
(1-4 fl. drs.). 

Mistura Rhei et Sodse (contains bicarbonate of soda, ipecac, peppermint 
and glycerin), 10-100 c.c. (2 fl. drs. -3 oz.). 

SZZlZL. i™,,™™ ) Dose for child 4-10 c.c. (1-2 fl. drs.). 



Syrupus Rhei Aromaticus 

B. P. — Rhei Radix, rhubarb root, the erect rhizome or so-called root of 
Rheum palmatum ; 3-10 grs. for repeated administration ; for a single ad- 
ministration, 15-30 grs. 

Extractum Rhei, 2-8 grs. 

Pilula Rhei Composita (contains rhubarb, Socotrine aloes, myrrh, and 
oil of peppermint), 4-8 grs. 

Pulvis Rhei Compositus (Gregory's Powder) contains rhubarb, light 
magnesia and ginger, 20-60 grs. 

Tinctura Rhei Composita, formed from rhubarb, cardamom and cori- 
ander, J-l fl. dr. for repeated administration ; 2-4 fl. drs. for a single ad- 
ministration. 

Syrupus Rhei, |-2 fl. drs. 

Infusum Rhei, |-1 fl. oz. 

Liquor Rhei Concentratus, |— 1 fl. dr. 

Tj. s. P. — Senna, the leaflets of Cassia acutifolia (Alexandria Senna), and 
of Cassia angustifolia (India Senna). 

1 For the reactions required to distinguish chrysophanic acid in the urine from the 
pigment occurring in it after santonin, see page 124. 



VEGETABLE PURGATIVES. 103 

Confectio Senn^ contains senna, cassia fistula, tamarind, prune fig 
sugar, and oil of coriander, 4-8 G. (1-2 drs.). 
Extr actum Sennse Fluidum, 4-8 c.c. (1-2 fl. drs.). 

Infusum Sennse Compositum (Black Draught) contains senna, manna, 
magnesium sulphate and fenuel, 60-120 c.c. (2-4 fl. oz.). 

Syrupus Senn^:, 4-16 c.c. (1-4 fl. drs.). 

Senna is also contained in the compound syrup of sarsaparilla and in the 
compound liquorice powder. 

Senna is often administered as a simple infusion, senna tea, a teaspoon ful 
of the leaves being used in a cupful of water. 

B. P. — Senna Alexandrina, the dried leaflets of Cassia acutifolia. 

Senna Indica, Tinnivelly senna, the dried leaflets of Cassia angustifolia. 

Tinctura Sennse Composita, formed from senna, raisins, caraway, and 
coriander, J-l fl. dr. for repeated administration ; 2-4 fl. drs. for a single 
administration. 

Syrupus Sennse, J-2 fl. drs. 

Liquor Sennse Concentratus, J-l fl. dr. 

Infusum Senn,e, J-l fl. oz. ; as a draught, 2 fl. oz. 

Mistura Senn^: Composita (Black Draught), formed from magnesium 
sulphate, liquorice, compound tincture of cardamom, aromatic spirit of 
ammonia, and infusion of senna, J-2 fl. oz. 

Confectio Sennse, formed of senna, coriander, figs, tamarinds, cassia, 
prunes, liquorice, and sugar, 60-120 grs. 

U. S. P. — Aloe Socotrina, the inspissated juice of the leaves of Aloe Perryi. 

Aloe Barbadensis, the inspissated juice of the leaves of Aloe vera. 

The preparations of aloes are all formed from Socotrine Aloes. 

Aloe Purificata, Socotrine aloes from which insoluble impurities have been 
removed, 0.1-0.5 G. (2-7 grs.). 

Aloinum, either Barbaloin or Socaloin, 0.05-0.2 G. (1-4 grs.). 

Extr actum Aloes, 0.1-0.5 G. (2-7 grs.). 

Pilule Aloes, 1-5 pills. 

Pilul.e Aloes et Asafoztid^e, 1-5 pills. 

Pilulse Aloes et Ferri, 1-5 pills. 

Pilulse Aloes et Mastiches, 1-5 pills. 

Pilulse Aloes et Mxjrrhse, 1-5 pills. 

Tinctura Aloes, 2-8 c.c. (J-2 fl. drs). 

Tinctura Aloes et Myrrhae, 2-8 c.c. (J-2 fl. drs.). 

Aloes is also contained in compound rhubarb pill, compound extract of 
colocynth and compound tincture of benzoin. 

B. P. — Aloe Barbadensis, the juice of Aloe vera and other species, Bar- 
badoes Aloes or Curacoa Aloes, 2-5 grs. 

Aloe Socotrina, the juice of Aloe Perryi, Socotrine or Zanzibar Aloes. 

Aloinum, J-2 grs. 

Extractum Aloes, 1-4 grs. 

Pilula Aloes, 4-8 grs. 

Pi I u la Aloes Socot rinse, 4-8 grs. 

Pilula Aloes et Ferri, 4-8 grs. 

Pilula Aloes et Asafetid.e, 4-8 grs. 

Pilula Aloes et Mxjrrhse, 4-8 grs. 

Tinctura Aloes, J-l fl. dr. for repeated doses; for a single dose, l.\-2 II. drs. 

Decoct um Aloes Compositum (aloes, myrrh, saffron, potassium carbonate, 
liquorice, compound tincture of cardamom), J-2 fl. oz. 

Aloes is also contained in the compound extract of colocynth, compound 
colocynth pill, pill of colocynth and hyoscyamus, compound gamboge pill, 
compound tincture of benzoin and compound rhubarb pill. Some of the 
preparations are directed to be made from Socotrine, others from Barbadoea 
aloes, but there is really no difference in the effects. 

U. S. P. — Frangula, Buckthorn, the bark of Bhamnus frangula, collected 
at least one year before being used. 



104 ORGANW SUBSTANCES ACTING LOCALLY. 

Extractum Frangulse, Fluidum, 1-2 c.c. (15-30 mins.). 

U. S. P. — Rhamnus Purshiana, Cascara sagrada, the bark of Rhamnus 
Purshiana. 

Extractum Rhamni Purshiana Fluidum, 1-2 c.c. (15-30 mins.). 

B. P. — Cascara Sagrada, the dried bark of Rhamnus Purshianus. 

Extractum Cascarse Sagradte, 2-8 grs. 

Extractum Cascara Sagradte Liquidum, |-1 fl. dr. 

Syrupus Cascarve Sagradm Aromaticus, J-2 fl. drs. 

An artificial compound, formed by combining- a trioxyanthraquinone with 
acetic acid, has recently been introduced under the uninviting name of pur- 
galin. It is quite insoluble in water and tasteless but is decomposed in the 
intestine and acts there like the other purgatives, to which it does not seem 
superior. Dose, 0.5-1.0 G. (8-15 grs.). 

Of these numerous preparations, the most extensively prescribed are 
the pills. The fluid preparations have an unpleasant, bitter taste, and 
are therefore less used, unless when disguised by the addition of sugar 
or volatile oils. The syrups of rhubarb and senna are often admin- 
istered to children, and the confection of senna and the compound 
liquorice powder are also pleasant, easily taken preparations. The 
compound infusion or mixture of senna and the compound rhubarb 
powder are old and tried preparations, in which the virtues of the 
vegetable purgative are combined with those of a saline cathartic and 
antacid respectively ; they are both possessed of a harsh, unpleasant 
taste. Frangula is comparatively rarely used, but the fluid extract of 
cascara sagrada, which is practically identical with it, is a very popular 
remedy in habitual constipation. 

Pure Chrysophanic Acid is not adapted for use as a purgative, as even in 
doses of 0.3 G. it fails to increase the peristalsis. A compound of chryso- 
phanic acid, Chrysarobin (C 30 H 26 O 7 ), has found employment as an application 
in some forms of skin disease, especially in psoriasis, in which it is often of 
marked benefit. It is found in an impure form (Goa powder) in cavities in 
the Andira araroba, a tree growing in India and Brazil, and is isolated with 
comparative ease ; it forms chrysophanic acid when it is oxidized. Chrysa- 
robin is much more irritant than chrysophanic acid, and applied to the skin 
in a concentrated form, or in susceptible persons, causes itching, redness and 
swelling, less frequently papular or pustular eruptions ; the skin and cloth- 
ing are stained a reddish-brown color where it is applied. When swallowed, 
chrysarobin acts as a gastro-intestinal irritant, causing vomiting and purg- 
ing ; some of it is absorbed, and in its excretion by the kidneys causes in the 
rabbit nephritis with albumin and even blood in the urine. In man, slight 
albuminuria has been observed in some instances after its application to the 
skin ; in animals the epithelium of the renal tubules has been found to be 
necrosed, the glomeruli being less frequently affected. It was anticipated 
that it would undergo oxidation to chrysophanic acid in the body, and this 
is true for a part of that absorbed, but most of it passes through the tissues 
unchanged. 

Anthrarobin, an artificial derivative of alizarin, was advised at one time as 
a substitute for chrysarobin and chrysophanic acid in the treatment of psori- 
asis and other forms of skin disease, but its value has been disputed and it is 
comparatively seldom used now. Pyrogallol apparently acts in the same 
way in psoriasis as chrysarobin, and the effect has in each case been attrib- 
uted to the withdrawal of the oxygen from the diseased skin. 

Araroba (B. P.), or Goa powder, a substance found in cavities in the trunk 
of Andira araroba, free from fragments of wood, dried and powdered. 



VEGETABLE PUEGA TIVES. 1 1 )."> 

Chrysarobinum (B. P.), a substance obtained from Araroba by extracting 
with hot chloroform, and evaporating. It consists for the most part of 
chrysarobin, but contains some chrysophanic acid. 

Unguentum Chrysarobini (B. P.), 4 per cent. 

Chrysarobin is used in skin diseases, especially in psoriasis, in which 
it is applied in ointment. Chrysophanic acid might be used also for 
this purpose were its isolation not attended with such expense. Some 
confusion has arisen from chrysarobin having been at first supposed to 
be chrysophanic acid. 

3. The Jalapin and Colocynthin Group. 

The third group of the vegetable purgatives comprises a number of 
resinous bodies, from several of which Buchheim succeeded in form- 
ing acids by treatment with alkalies and afterwards with acids. He 
found most of the acids formed from these resins devoid of purgative 
action, and this led him to believe that the bodies existing in nature 
were anhydrides, and that their irritant effects were associated with 
their anhydride constitution. The chemistry of these bodies is still 
very obscure, however, and it is possible that the changes produced 
by his treatment do not consist only in hydration. On the other hand, 
some substances which Buchheim supposed inactive have proved to 
possess purgative properties. Thus Stadelmann found that the sodium 
salts of jalapinic and convolvulinic acids produce evacuation of the 
bowel in dogs, although nearly three times as much is required for 
this effect as of jalapin and convolvulin. It would seem, therefore, 
that Buchheiro's explanation must be abandoned. A number of these 
bodies appear to be nearly related chemically, and it is possible that 
they, like those of the anthracene group, contain a common radical. 
In most instances these purgative substances are glucosicles. 

Jalap resin contains two anhydride glucosides, Convolvulin and Jalapin, the 
latter only in very small quantity. Scammony consists very largely of Jala- 
pin. Squirting cucumber contains a resin (elaterium), the active principle of 
which is Elaterin, another anhydride of which little is known. Podophyl- 
lum contains two isomeric glucosides, Podophylloto.vin and PicropodophyUia 
(C 23 H 24 9 ). Gamboge owes its activity to Cambogic acid, which, however, is 
insoluble, and seldom acts unless it is accompanied by the inactive bodies of 
the crude drug. Colocynthin is a giucoside occurring in the eolocynth fruit. 
and forms Culocynthein and sugar when treated with acids. Colocynthein is 
said to be even more irritant than colocynthin. Bryony contains two gluco- 
sides. Bryonin and Bryonidin. of which the latter is the more active. Lep- 
fcandra owes its activity to a resinous giucoside. Leptandrin. euonynms to a 
giucoside, Euonymin. Many other plants contain similar resinous purgative 
substances, and some of these are used as remedies to some extent, but so 
little is known of their properties and they are so seldom employed that they 
may be omitted here. 

Action. — These substances are in general much more powerful than 
any of the other purgatives except croton oil, and are therefore classed 
along with the latter as the drastic purgatives or hydragoguc cathar- 



106 OR GA NIC S UBSTANCES A CTING L OCA LL Y. 

tics. In small quantities they cause evacuation more rapidly than the 
anthracene purgatives, and in somewhat larger doses produce profuse 
watery stools with much pain and often tenesmus. In cases of poison- 
ing, the bowel undergoes acute inflammation, and blood is passed in 
the stools, which often contain shreds of epithelium from the walls. 
The irritant action is not confined to the bowel apparently for their 
administration is sometimes- followed by uneasiness in the stomach, 
and occasionally by nausea and vomiting. On the other hand, mod- 
erate quantities are said not to induce colic so frequently as some of 
the anthracene purges. 

Several of these resinous purges are irritant to the skin and especially to 
the mucous membranes of the eye, nose and throat. Thus jalap, podophyl- 
lum and colocynthin all cause pain and irritation when they are applied to 
the nostrils in fine powder, and podophyllum has been used as a skin irri- 
tant. 

The presence of bile in the intestine increases the purgative action of al- 
most all these bodies, and in fact, seems absolutely necessary for the action 
of some of them. 

Podophyllotoxin and colocynthin cause purgation when injected subcu- 
taneously ; this is probably owing to their excretion into the bowel, as the 
former has been detected in the faeces after this method of administration. 
Podophyllotoxin causes glomerular nephritis and hemorrhages into various 
organs when administered hypodermically or intravenously in large quanti- 
ties, and when added to blood in a test-tube, it causes the formation of met- 
hsemoglobin in the corpuscles. It has been said to have a depressant action 
on the central nervous system, but this is probably a result of the shock and 
hemorrhage produced by its intestinal action. Colocynthin is said to cause 
renal inflammation when applied subcutaneously or taken internally, and 
even when the powder is inhaled during its manufacture. Jalapin and con- 
volvulin given by the mouth cannot be found in the faeces or urine, and are 
therefore supposed to undergo partial or complete oxidation in the body. 
Convolvulin is found in the urine, however, when it is injected intraven- 
ously, and no purgation follows this method of administration ; so that it is 
probable that convolvulin is decomposed in the bowel when it is adminis- 
tered internally. 

Euonymin has the same effect on the heart as digitalis, and will be men- 
tioned along with it, although it has a mild purgative action and is used 
chiefly as an aperient. 



Preparations. 

Colocynthis (TJ. S. P.), colocynth, the fruit of Citrullus Colocynthis de- 
prived of its rind. 

Colocynthidis Pulpa (B. P.), the dried pulp of the fruit of Citrullus Colo- 
cynthis freed from seeds. 

Extractum Colocynthidis (TJ. S. P.), 0.1-0.3 G. (2-5 grs.). 

Extractum Colocynthidis Compositum (U. S. P., B. P.) (containin 
colocynth, aloes, scammony and cardamom), 0.2-1 G. (3-15 grs.). 

Colocynthin, 5-10 mg. (Not pharmacopceial.) 

Pilule Cathartics Composite (TJ. S. P.) (contain compound extract 
of colocynth, jalap, gamboge and calomel), 1 pill as laxative ; 3 as drastic 
purgative. 

Pilule Cathartics Vegetabiles (TJ. S. P.) (contain compound extract 
of colocynth, Jalap, leptandra, podophyllum, hyoscyamus and oil of pep- 
permint), 1 pill as laxative ; 3 as drastic purgative. 



: 



t"=p 



VEGETABLE PURGATIVES. 107 

Pilula Colocynthidis Composita (B. P.), colocynth, Barbadoes aloes, 
scammony resin, potassium sulphate and oil of cloves, 4-8 grs. 

Pilula Colocynthidis et Hyoscyami (B. P.), compound pill of* colo- 
cynth and extract of hyoscyamus, 4-8 grs. 

Podophyllum (U. S. P.), Podophylli Rhizoma (B. P.), the rhizome and 
roots of Podophyllum peltatum. 

Extractum Podophylli (U. S. P.). 05-0.2 G. (1-3 grs.). 

Extractum Podophylli Fluidum (IT. S. P.), 0.3-1 c.c. (5-15 mins.). 

Resina Podophylli (U. S. P.), Podophylli Resina (B. P.), 15-60 mgs 
(1-1 gr.). 

Tinctura Podophylli (B. P.), 5-15 mins. 

Podophyllin varies considerably in composition, and ought to be avoided. 

Podophyllotoxin. 5-10 mgs. Neither of these is pharmacopoeia!. 

Jalapa (U. S. P., B. P.), the tuberous root of Ipomcea Jalapa. 0.3-1 G. 
(5-15 grs.). 

Extractum Jalapse Alcoholicum (IT. S. P.), Extractum Jalapse (B. P.), 0.1- 
0.5 G. (2-8 grs.). 

Resina Jalaps (U. S.P.), Jalapse Resina (B. P.), 0.1-0.3G. (2-5 grs.). 

Pulvis Jalaps Compositus (U. S. P., B. P.) contains jalap and bitar- 
trate of potash. 1-4 G. (15-60 grs.). 

Tinctura Jalapse (B. P.), \-l fl. dr. 

Scammonium (U. S. P.), a resinous exudation from the living root of Con- 
volvulus Scammonia. 

Resina Scammonise (IT. S. P.), 0.2-0.5 G. (3-8 grs.). 

B. P. — Scammonise Radix, Scammony root, the dried root of Convolvulus 
Scammonia. 

Scammonium, a gum resin obtained from the scammony root, 5-10 grs. 

Scammonise Resina, 3-8 grs. 

Pilula Scammonia Composita (contains jalap and ginger), 4-8 grs. 

Pulvis Scammonii Compositus (contains jalap and ginger), 10-20 grs. • 

Scammony is also contained in the compound colocynth preparations. 

Euonymus (U. S. P.), Euonymi Cortex (B. P.), Wahoo, the dried root- 
bark of Euonymus atropurpureus. 

Extractum Euonymi (IT. S. P.), 0.05-0.2 G. (1-3 grs.). 

Extractum Euonymi Siccum (B. P.). 1-2 grs. 

Elaterinum (U. S. P., B. P.), C 20 H 28 O 5 , a neutral principle obtained from 
elaterium, a substance deposited by the juice of the fruit of Ecballium Ela- 
terium (squirting cucumber). 1-5 mgs. (eWo g r -)- 

Trituratio Elaterini (IT. S. P.) (one part elaterin in 9 parts sugar of milk), 
•15-60 mgs. (i-1 gr.). 

Elaterium (B. P.), varies in strength, T y-| gr. 

Pulvis Elaterini Compositus (B. P.) (one part elaterin in 39 parts milk 
sugar), 1-4 grs. 

Cambogia (U. S. P., B. P.), Gamboge, a gum resin obtained from Garcinia 
Hanburii. 

Pilula Cambogise Composita (B. P.) contains Barbadoes aloes and cinnamon. 
4-8 grs. 

Bryonia (IT. S. P.), Bryony, the root of Bryonia alba and of Bryonia 
dioica. 

Tinctura Bryonise (IT. S. P.), 1-4 c.c. (15-60 mins.). 

Leptandra (IT. S. P.), Culver's root, the rhizome and roots of Veronica 
virginica. 

Extractum Leptandrse (IT. S. P.), 0.1-0.2 G. (2-4 grs). 

Extractum Leptandrse Fluidum (IT. S. P.) 2-4 c.c. (30-60 mins.). 

Two other purgatives may be mentioned here, although nothing is known 
regarding their active principles. 

Iris (IT. S. P.), the rhizome and roots of Iris versicolor, Blue Flag. 

Extractum Iridis (IT. S. P.), 0.1-0 2 G. (2-4 grs.). 

Extractum Iridis Fluidum (IT. S. P.), 0.5-1.5 c.c. (10-20 mins.). 



108 ORGANIC SUBSTANCES ACTING LOCALLY. 

Juglans (IT. S. P.), butternut, the bark of the root of Juglans cinerea. 
Extractum Juglandis (U. S. P.), 1-2 G. (15-30 grs.). Juglans is a com- 
paratively mild laxative. 

The resinous purgatives are generally administered in pill form ; 
very frequently two or more are combined in one pill, or they may be 
prescribed along with extract of belladonna or hyoscyamus, or with a 
drop of some carminative oil or resin, to prevent the pain and griping 
which often accompanies their action. The importance of these purga- 
tives is much less than it was formerly, and several of them are very 
seldom used ; the most important are colocynth, podophyllum, and 
jalap. In large doses they act rapidly, with the exception of podo- 
phyllum, which induces purgation very slowly (10-20 hours). 

Therapeutic Uses of the Purgatives. — The purgatives are employed 
to cause evacuation of the bowel when for any reason its peristalsis is 
slow. In ordinary constipation of short standing, in which the peri- 
stalsis may merely seem somew r hat more sluggish than usual, the milder 
laxatives are prescribed — castor oil, senna, rhubarb, aloes, frangula, or 
cascara sagrada. The first two cause least disturbance of the bowel, 
but are disagreeable to take, and are less commonly prescribed for 
adults than rhubarb or cascara, or small doses of colocynth or podo- 
phyllum. In children or in debility in adults, senna and castor oil 
are frequently used however. 

In chronic constipation which cannot be controlled by hygienic 
measures, or by the use of a special dietary such as fruits, or coarse 
meal, and where the intestine has apparently taken on a sluggish habit, 
rhubarb, cascara, aloes, podophyllum, or colocynth may be ordered, 
but the saline cathartics often prove more satisfactory. Rhubarb tends 
to cause some constipation after its laxative effects, but is often used in 
these cases, as it possesses some bitter stomachic action, which compen- 
sates for its astringent after-effects. This bitter action is often given 
to the other purgatives by the addition of gentian, nux vomica, or 
cinchona. In obstinate constipation, in which the bowel contains hard 
fsecal masses, the milder purgatives often provoke griping without 
relieving the condition, and in these cases larger doses of colocynth, 
jalap, podophyllum, or croton oil are used, along with some of the ex- 
tracts of the atropine group or with a carminative oil. They may be 
prescribed along with some of the saline cathartics, as in the compound 
infusion of senna or the compound powder of jalap. 

Croton oil is used especially where the drug is required to be of 
small bulk and the administration is attended with special difficulty ; 
thus in unconsciousness or mania one or two drops may be given on 
sugar. In lead colic, croton oil is said to act more rapidly and effi- 
ciently than the others. 

In some forms of diarrhoea constant irritation seems to be kept up 
by the presence of irritants in the bowel, and the indications are the 
removal of these by a purge rather than the administration of astrin- 
gents. Castor oil, senna, and rhubarb are especially adapted for this 
purpose ; the two first because they increase the irritation of the bowel 



VEGETABLE PURGATIVES. 109 

less than the others, the latter because of its subsequent astringent 
action. 

A purgative is often administered as a preliminary in the treatment 
of malaria, syphilis and other conditions, and seems to have beneficial 
effects, although these are difficult to explain. In the beginning of 
acute fevers also a purge is often useful, perhaps through the co 
tion of the bowel withdrawing the blood from the rest of the body, or 
through the removal of poisonous substances formed by the decompo- 
sition of the intestinal contents. In congestion of the brain a purga- 
tive is often administered with good effects, which may also be attributed 
to the accumulation of blood in the mesenteric circulation, and perhaps 
to some action analogous to counter-irritation of the skin. For these 
purposes a sharp purge is generally used, either croton oil or one of 
the jalapin and colocynthin series. 

The more powerful purgatives were formerly largely used to remove 
fluid from the body in cases of dropsy or oedema, and they were gener- 
allv prescribed along with the saline cathartics for this purpose. The 
violent action required is weakening, however, and while the fluid is 
withdrawn to a greater or less extent, the condition of the patient often 
undergoes little improvement, so that this measure is comparatively 
seldom used now. 

The congestion of the pelvic organs induced by these purges is not 
infrequently beneficial in cases of amenorrhoea. Aloes is almost exclu- 
sively used for this purpose, and is generally administered along with 
iron or with myrrh, which is credited with some special action on the 
genital organs. 

The purges act as intestinal disinfectants by removing the micro- 
organisms mechanically, though the vegetable purges are less used 
for this purpose than calomel. A purgative is administered to remove 
poisons in the intestine when they have passed beyond the stomach 
or when they are excreted into the bowel. 

Purgatives are contraindicated in conditions of acute intestinal irri- 
tation, and during menstruation and pregnancy, owing to the conges- 
tion of the pelvic organs, which may lead to an excessive flow in the 
one case and to abortion in the other ; aloes is especially dangerous 
in these conditions. In collapse, asthenia and anaemia, powerful pur- 
gatives are contraindicated, owing to the irritation they produce. 
In haemorrhoids, aloes is often said to do harm by increasing the con- 
gestion of the rectum, and powerful purges are injurious from the 
straining they cause, but if constipation is present, a mild purgative is 
beneficial. In all those conditions, if a purgative is required, either 
castor oil, senna or rhubarb ought to be chosen. 

Repeated attempts have been made to produce evacuation of the bowels 
by substances injected subcutaneously. Hiller found colocynthin the best 
available for practical purposes, although aloin and cathartinic acid also 
acted efficiently. The injection is so painful, however, that it ought only to 
be had recourse to in exceptional circumstances. 

Another method by which the purgatives may be administered is in enema. 



110 ORGANIC SUBSTANCES ACTING LOCALLY. 

The addition of purgatives, such as castor oil, and of bile to the ordinary- 
en emata has been practised for many years, but Kohlstock has recently 
drawn attention to the use of purgatives by enema with only 1-3 teaspoonfuls 
of fluid. The large water enema, containing a pint or more of fluid, acts 
mainly by distending the bowel and thus setting up peristalsis, although the 
soaps, salt and other similar bodies, which are often added to it, may have 
an irritating effect in addition. In the small enema, however, distention 
plays no part, the movement being elicited by the irritant action of the drug. 
Kohlstock found that colocynthin (0.01-0.03 G.), aloin (0.4-0.5 G.), and 
cathartinic acid (0.6 G.) dissolved in glycerin caused purgation, colocynthin 
acting in J-2 hrs., aloin in 2-12 hrs. and cathartinic acid in 1-6 hrs. The 
two latter were certain in their effects only in cases of moderate constipation. 
He attributes their action to absorption from the rectum. 

Bibliography of the Vegetable Purgatives. 
Purgative action in general. 

Thiry. Wiener Sitzungsbericht. Mathemat-naturwiss. Classe, Bd. L., Abt. i., p. 77. 
Radziejewski. Arch. f. Anat. u. Phys., 1870, p. 37. 
Hess. Deutsch. Arch. f. klin. Med., xl., p. 93. 
Brieger. Arch. f. exp. Path. u. Pharm., viii. , p. 355. 
Brandl u. Tappeiner. Ibid., xxvi., p. 177. 
Brunton. Practitioner, xii., p. 342. 

Stadelmann. Berliner klin. Woch., 1896, p. 181. Archiv f. exp. Path. u. Pharm., 
xxxvii., p. 352. 

Buchheim. Arch. f. Heilkunde, xiii., p. 1, and xiv. , p. 1. 
Wood. Amer. Jo-urn. of Med. Sciences, lx., p. 75. 
Hiller. Zeitschr. f. klin. Med., iv., p. 481. 
Kohlstock. Charite-annalen, xvii., p. 283. 

Purgative oils. 

Buchheim. 1. c. 

Meyer. Arch. f. exp. Path. u. Pharm., xxviii., p. 145 ; xxxviii., p. 336. 

Kobert'u. Hirschheydt. Arb. des pharmak. Institutes zu Dorpat, iv., p. 5. 

Anthracene purgatives. 

Aloin. Meyer. Arch. f. exp. Path. u. Pharm., xxviii., p. 186. 
Kohn. Berl. klin. Woch., 1882, p. 68. 
Murset. Archiv f. exp. Path. u. Pharm., xix., p. 310. 
J'.'sselmont. Ibid., xliii., p. 274. 

Tschirch. Bericht. d. deutsch. pharmaceut. Gesellsch., 1898, p. 174. 
Senna. Kubly. Inaug. Diss., Dorpat, 1865. 
Stockman. Arch. f. exp. Path. u. Pharm., xix., p. 117. 
Gensz. Inaug. Diss., Dorpat, 1893. 
Vieth. Munch, med. Woch., 1901, No. 35. 
Frangula. Baeumker. Inaug. Diss., Gottingen, 1880. 

Chrysarobin and Anthrarobin. Lewin u. Rosenthal. Virch. Arch., lxxxv., 
p. 118. 

Midler. Munch, med. Woch., 1896, p. 1221. 
Weyl. Pfluger's Arch., xliii., p. 367. 
Koch. Inaug. Diss., Giessen, 1880. 

Jalapin and Colocynthin Series. 

Podophyllum. Podwyssotzki. Arch. f. exp. Path. u. Pharm., xiii., p. 29. 
Neuberger. Ibid., xxviii., p. 32. 
Kursten. Archiv der Pharm., ccxxix., p. 220. 
Spindler. Inaug. Diss., Dorpat, 1893. 
Jalap. J. Midler. Inaug. Diss., Dorpat, 1885. 

Scher. Inaug. Diss., Dorpat, 1895; Virchow-Hirsch Jahresber., 1895, p. 380. 
Colocynth. Hagentorn. Inaug. Diss., Dorpat, 1857. 
Elaterium. Kohler. Virch., Arch., xlix., p. 408. 

Bryonia. Mankowsky. Historische Studien a. d. pharmakol. Instit., Dorpat, ii., 
p. 143. 



VEGETABLE ASTRINGENTS— TANNIC ACID SERIES. Ill 

VII. VEGETABLE ASTRINGENTS — TANNIC ACID SERIES. 

A large number of vegetable substances owe their action to their 
containing tannin substances, while in many other preparations the ef- 
fect of more important constituents is modified by the presence of 
these widely distributed bodies. Tannic acid proper is derived from 
the oak gall, and seems to consist of an anhydride combination of 
gallic acid, into which it is very easily decomposed, probably according 
to the following equation : 

Tannic acid. Gallic acid. 

C 6 H 3 (OH) 3 CO — 0(OH) 2 C 6 H a COOH + H 2 = 2C 6 H 2 (OH 3 )COOH. 

Gallic acid is formed from a large number of other bodies which 
closely resemble tannic acid in their general features, but are by no 
means identical with it. Their constitution is altogether unknown, 
but they possess a number of reactions in common and are generally 
classed together as the tannic acid substances. Some of them contain 
a sugar, and tannin or tannic acid is therefore sometimes said to be a 
glucoside. These bodies precipitate albumins, gelatins, alkaloids and 
some glucosides, and the salts of the heavy metals. The salts of iron 
form a bluish-black or greenish-black precipitate, and an attempt is 
sometimes made to divide the forms of tannic acid by this reaction, 
but they may be better indicated by their origin, as kinotannic acid 
from kino, catechutannic acid from catechu, etc. 

Action. — The pharmacological effects of these bodies are due to 
their precipitating albumins and other proteids, and this reaction 
may therefore be described before their action in the body. If 
tannic acid solution be added to a neutral solution of albumin or 
gelatin, a white precipitate falls, which is entirely insoluble in water, 
but is soluble in excess of albumin or gelatin, in acetic or lactic acid, 
and in alkaline solutions. 1 Solutions of pepsin and of peptones are also 
precipitated by tannic acid unless in the presence of an acid. If pro- 
teid tannate be exposed to the action of the gastric juice it undergoes 
digestion and is dissolved in the same way as an ordinary coagulated 
proteid such as fibrin. During the process the tannic acid is set free 
from its combination apparently, and can precipitate undigested pro- 
teids, although it has no effect on the peptones in the acid medium. 
When a soluble tannate is formed by the addition of soda or potash to 
a tannic acid solution, the presence of proteids produces no precipitate, 
the affinities of the acid being satisfied by the alkali, and for the same 
reason the tannic acid precipitate is dissolved in the presence of 
alkalies. 

Tannic acid applied to animal tissue, as in the tanning of leather, 
causes a precipitation of the proteids, and the tissue becomes harder 
and tougher and tends to shrink together ; at the same time it has less 
tendency to undergo putrefactive changes and does not lose its flexi- 

^orae discrepancies in the accounts of different authors in regard to these reactions 
are perhaps due to variations in the amount of the neutral salts in their preparations. 
The account given by Lewin has been followed in the text. 



112 ORGANIC SUBSTANCES ACTING LOCALLY. 



liate 
•ther 



bility, as it would in drying. Strong solutions cause an immediate 
dense precipitate of the proteids on the surface and prevent the further 
penetration of the coagulating fluid, while the more dilute solutions are 
believed to penetrate more deeply and thus to cause a more complete 
precipitation of the proteids of the tissue. 

Tannic acid solutions have a harsh, bitter, "astringent" taste and 
produce in the mouth a feeling of constriction, dryness and rough- 
ness, along with a sense of stiffness in the movements of the tongue, 
and some loss of taste. These effects are due to the coagulation of the 
superficial layers of proteid both within and without the epithelium, 
which substitutes for the ordinary smooth surface a firmer, less even 
one, over which the tongue can no longer move easily. The feeling 
of constriction may, perhaps, be caused by an actual shrinking of the 
superficial layers of the epithelium, or may be due merely to the im- 
paired movements and sensation. 

The astringent feeling is continued in the throat as the solution is 
swallowed, and occasionally some discomfort or even nausea and vomit- 
ing are provoked by it, but as a general rule no such effects are observed. 
The stools are rendered harder and firmer by the administration of 
tannic acid, and constipation is often produced by it. In excess, tannic 
acid sometimes causes irritation of the intestine and diarrhoea, but 
beyond these symptoms of local irritation of the stomach and bowel, 
no effects arise from even enormous quantities of the drug. 

In the stomach, tannic acid combines with any proteid substance with 
which, it may come in contact and precipitates it, but as digestion pro- 
gresses, this combination is broken up, as the peptones do not combine 
with tannic acid in acid solution, and the astringent action is therefore 
exercised on the walls of the stomach and intestine. Ordinary quanti- 
ties cause the same superficial coagulation as in the mouth, but if large 
doses be given when the stomach and intestine are not protected by 
foodstuffs, a more complete coagulation of the mucous membrane takes 
place and the consequent irritation results in vomiting, and sometimes 
in diarrhoea. The increase in the consistency of the stools is probably 
due to the layer of coagulated proteid acting as a protective to the 
bowel, lessening its irritability and thus retarding its movements, so 
that there is longer time for the absorption of the fluid part of its 
contents, although this proceeds more slowly under tannic acid than 
normally (Gebhardt). Yeasts and microbes are precipitated by tannin, 
and this may tend to lessen the fermentations in the bowel in some 
cases, although some preparations of tannic acid which have been ex- 
amined in regard to this point have been found to have little or no 
effect on intestinal putrefaction. 

The local application of tannic acid causes a diminution of the se- 
cretions of glands, as has been demonstrated by Schutz. This is due 
to its effects upon the protoplasm of the secreting cells, which probably 
undergo the initial stages of coagulation. 

It was formerly believed that tannic acid caused constriction of the 
vessels of any part to which it was applied, but some doubt has been 



VEGETABLE ASTRINGENTS— TANNIC ACID SERIES. 113 

thrown on this by the experimental results obtained by Rosenstirn and 
others. Heinz, the most recent writer on the subject, found that 
solutions of tannic acid of less strength than J per cent, caused con- 
striction of the mesenteric vessels of the frog or rabbit when applied 
directly, while more concentrated solutions caused transient constric- 
tion followed by dilation. Another local effect produced by tannic 
acid is seen in the cessation of the movements of the leucocytes in the 
tissues around the point of application and the arrest of their diapedesis 
through the walls of the vessels. 

When tannic acid comes in contact with blood in a test-tube it pre- 
cipitates the albumins, and when it is injected intravenously, the precip- 
itate formed leads to the formation of emboli. The alkaline tannatcs 
are generally believed to be entirely devoid of astringent effects, unless 
when the tannic acid is freed from the combination by the presence of 
an acid, but according to Heinz and Gottlieb the astringent action is 
only weakened and not entirely removed by combination with the 
alkalies. 

The fate of tannic acid in the body has given rise to some discussion. 
When it is taken internally a small proportion is sometimes eliminated 
by the bowel unchanged, but very often none is to be found in the 
stools ; traces are apparently absorbed and excreted in the urine as so- 
dium tannate in both man and animals, although some investigators 
have failed to detect these. When sodium tannate is administered in- 
ternally, a distinctly larger amount of it is absorbed and reappears in 
the urine. But much the greater part of the tannic acid is decomposed 
in the intestine into gallic acid, some of which often passes out in the 
stools, some in the urine. Only about one per cent, of the tannic acid 
swallowed reappears in the excretions, either as tannic or gallic acid ; 
the rest apparently undergoes complete oxidation in the tissues, for no 
further trace of it can be found. After tannic acid is administered, 
some tannic or gallic salt is present in the blood, for iron salts give a 
darker color to it, but it is impossible to state whether this is tannin 
or a gallate, although in all probability it is the latter. According to 
Harnack, the gallic acid in the urine sometimes forms pyrogallol on 
standing, but this poisonous substance is not formed from tannic acid 
in the intestine or tissues. 

Tannic acid then does not exist in the tissues as such, but only in 
the form of traces of the gallate or tannate of soda, which are so small 
as to be devoid of astringent properties. Tannate of soda seems to 
have no action whatever, while gallic acid has no further properties 
than other weak acids. Theoretically, therefore, it is to be expected 
that the effects of tannic acid are limited to the point of application, 
and there is no evidence of any weight that it exercises any action after 
absorption. 

Lewin states that the muscles of the frog are altered in elasticity after the 

application of tannic acid subcutaneously, and an old observation is recorded 

in which the spleen was supposed to undergo contraction when tannic acid 

was administered, but the methods adopted render these observations worth- 

8 



114 ORGANIC SUBSTANCES ACTING LOCALLY. 

less. Tannic acid is often said to lessen the albuminuria in certain forms of 
Bright' s disease, but the only exact determinations which have been made 
in man showed that no such effect was present, and in Ribberts' experiments 
the animals were moribund when the improvement occurred, and no safe 
deductions can be made therefore. The urine is sometimes said to be 
diminished by tannic acid, but this statement is based on error. Last of 
all, tannic acid is said to lessen internal hemorrhage by contracting the 
vessels, but tannate of soda, the only form in which it can exist in the blood 
is entirely devoid of action. 

Gallic acid given by the mouth is absorbed and is excreted by the kidneys 
to some extent. Much of it disappears in the tissues, however, apparently 
by oxidation. The excretion of uric acid in the urine is considerably reduced 
by the administration of gallic acid. 

The numerous preparations of the pharmacopoeias which owe their 
activity to their containing tannic acid, differ from the pure drug in that 
the acid is only slowly dissolved out from the colloid mass, and there- 
fore acts less on the stomach and affects a greater length of intestine. 

Preparations. 

Acidum Tannicum (TJ. S. P., B. P.), tannic acid, gallotannic acid or digallic 
acid (HC 14 H 9 9 ), an organic acid obtained from nut gall, 0.1-0.6 G. (2-10 
grs.). 

Glyceritum Acidi Tannici (U. S. P.), Glycerinum Acidi Tannici 
(B. P.). 

Unguentum Acidi Tannici (U. S. P.). 

Collodium Stypticum (U. S. P.). 

Trochisci Acidi Tannici (U. S. P.), 0.06 G. (1 gr.) ; (B. P.), % gr. in each. 

Suppositoria Acidi Tannici (B. P.), 0.2 G. (3 grs.) in each. 

Acidum Gallicum (U. S. P., B. P.), gallic acid (HC 7 H 5 5 ), an organic acid 
usually prepared from tannic acid, has no astringent properties, nor, in fact 
any qualities which render it of value in medicine. 

Catechu (U. S. P.), an extract prepared from the wood of Acacia Catechu, 
1-2 G. (15-30 grs.). 

Tinctura Catechu Composita (U. S. P.) (flavored with cinnamon), 2- 
12 c.c. (|-3 fl. drs.). 

Trochisci Catechu (U. S. P.). 

Catechu contains catechutannic acid and catechin, a compound of tannic 
acid which gives most of the tannic acid reactions, but does not precipitate 
gelatin. 

Catechu (B. P.), an extract of the leaves and young shoots of Uncaria 
Gambier. 

Tinctura Catechu, J-l fl. dr. 

Trochiscus Catechu, each containing 0.065 G. (1 gr.) of catechu. 

Pulvis Catechu Compositus contains catechu, kino, krameria, cinnamon and 
nutmeg, 10-40 grs. 

Krameria (TJ. S. P.), Rhatany, the root of Krameria triandra and of 
Krameria Ixina, Kramerise Radix (B. P.), the dried root of Para Rhatany 
(Krameria argentea?) or of Peruvian Rhatany (Krameria triandra). 

Extractum Krameria (U. S. P., B. P.), 0.3-1 G. (5-15 grs.). 

Extractum Kramerise Fluidum (U. S. P.), 0.5-4 c.c. (10-60 mins.). 

Tinctura Kramerise (TJ. S. P., B. P.), 2-8 c.c. (J-2 fl. drs.). 

Syrupus Kramerise (TJ. S. P.), 2-10 c.c. (J-3 fl. drs.). 

Liquor Kramerise Concentratus (B. P.), J-l fl. dr. 

Infusum Kramerise (B. P.), ^-1 fl. oz. 

Trochisci Kramerise (TJ. S. P., B. P.). 

Trochiscus Kramerise et Cocainse (B. P.), each containing -^ gr. of cocaine. 



VEGETABLE ASTRINGENTS— TANNIC ACID SERIES. 115 

Kino (U. S. P., B. P.), the inspissated juice of Pterocarpus Marsupium 
0.5-2 G. (10-30 grs.). 

Tinctura Kino (U. S. P., B. P.), 2-8 c.c. (J-2 fl. drs.). 

Pulvis Kino Compositus (B. P.), contains 5 per cent, of opium, 5-20 grs. 

Hamamelis (U. S. P.), Hamamelidis Folia (B. P.), Witchhazel, the leaves 
of Hamamelis Virginiana, contains tannic acid, a volatile oil and a bitter. 

Hamamelidis Cortex (B. P.), the dried bark of Hamamelis Virginiana, witch- 
hazel bark. 

Extractum Hamamelidis Fluidum (TJ. S. P.), 2-8 c.c. (£-2 fl. drs.). 

Extractum Hamamelidis Liquidum (B. P.), 5-15 mins. 

Liquor Hamamelidis (B. P.). 

Tinctura Hamamelidis (B. P.), J-l fl. dr. 

Unguentum Hamamelidis (B. P.). 

Haematoxylon (U. S. P.), Haematoxyli Lignum (B. P.), Logwood, the 
heart-wood of Haematoxylon campechianum. 

Extractum Hsematoxyli (TJ. S. P.), 0.5-2 G. (10-30 grs.). 

Decoctum Hsematoxyli (B. P.), J-2 fl. oz. 

Eucalypti Grummi (B. P.), a ruby-colored exudation, or so-called red gum, 
from the bark of Eucalyptus rostrata and some other species of Eucalyptus. 
2-5 grs. 

Trochiscus Eucalypti Gummi (B. P.), each containing 1 gr. of the gum. 

Geranium (U. S. P.), Cranesbill, the rhizome of Geranium maculatum. 
1-2 G. (15-30 grs.). 

Extractum Geranii Fluidum (TJ. S. P.), 2-4 c.c. (30-60 mins.). 

Rubus (U. S. P.), Blackberry, the bark of the root of Rubus villosus, R. 
Canadensis and R. trivialis. 

Extractum Rubi Fluidum (TJ. S. P.), 2-8 c.c. (£-2 fl. drs.). 

Syrupus Rubi (TJ. S. P.), 2-8 c.c. (f-2 fl. drs.)" 

Galla (U. S. P., B. P.), Nut-gall, an excrescence on Quercus lusitonica 
(Quercus infectoria, B. P.), one of the oaks, caused by the punctures and 
ova of an insect, Cynips Gallse tinctorise. 

Tinctura Gallse (TJ. S. P.), 2-12 c.c. 

Unguentum Gallse (TJ. S. P., B. P.). 

Unguentum Gallse cum Opio (B. P.) contains 7J per cent, of opium. 

Castanea (TJ. S. P.), Chestnut, the leaves of Castanea dentata. 

Extractum Castanese Fluidum (TJ. S. P.), 2-4 c.c. 

Quercus alba (TJ. S. P.), white oak bark. 

Rhus glabra (TJ. S. P.), the fruit of sumach. 

Extractum Rhois Glabrse Fluidum (TJ. S. P.). 

Rumex (TJ. S. P.), yellow dock, the root of Rumex crispus and of some 
other species of Rumex. 

Extractum Rumicis Fluidum (TJ. S. P.), 2-4 c.c. 

Several new preparations of tannic acid have been introduced into thera- 
peutics of late years, chiefly for use as intestinal astringents. Tannic acid 
itself is liable to produce irritation of the stomach, and to be decom- 
posed or absorbed to a large extent before it reaches the large intestine, and 
although the cruder preparations are less liable to these changes, even they are 
by no means devoid of disagreeable features. Meyer, therefore, introduced 
tannigen, or diacetyltannin, in which two of the original hydroxy! groups of 
the tannic acid are replaced by acetyl. This body is exceedingly insoluble in 
water, but is dissolved by alkalies. It was hoped that it would remain insol- 
uble in the stomach and only commence to act in the bowel, and Rost finds 
that after administration by the mouth, it occurs in the human faeces in small 
quantity as tannic acid, while in the cat it passes through tin 4 alimentary 
canal in part unchanged. At the same time the presence of gallic acid in the 
urine indicates that part of it undergoes the fate of tannic acid. Tannoform 
is a somewhat similar combination of tannic acid and formaldehyde, while 
tannopin is a still more recent and untried member of the series. Both 



116 ORGANIC SUBSTANCES ACTING LOCALLY. 

tannigen and tannoform are astringent in the mouth and stomach, but reach 
the bowel owing to their insolubility. The tannalbin of Gottleib, on the 
other hand, is a combination of tannic acid and albumen, dried at such a 
temperature as to prevent the action of the gastric juice upon it, but capable 
of being broken up by the more powerful pancreatic fluids. It is entirely 
insoluble and is not astringent until digested in the bowel, so that it has no 
irritant action on the stomach and is tasteless. Rost found tannalbin and 
tannic acid in the faeces of the cat after its administration, while only gallic 
acid occurs in the stools and urine in man, showing that in the latter the 
whole of the tannalbin administered is decomposed in its passage through 
the alimentary canal. Tannocol is a combination of tannic acid and gelatin, 
resembling tannalbin in most respects. 

Tannigen, 0.5-2 G. (10-30 grs.), in powder. 
Tannalbin, 0.5-2 G. (10-30 grs.), in powder. 

Several combinations of gallic acid have been introduced of late years as 
astringents. They can have no such effect, however, and must be regarded 
as additions to the group of inert protective powders, which is already rep- 
resented in overabundance in therapeutics. 

Therapeutic Uses. — The preparations of tannic acid ought to be used 
for their local effects exclusively. They are applied externally in 
cases of excessive secretion, as in local sweating or weeping ulcers, and 
occasionally to harden the skin. For this purpose tannic acid may be 
used in solution in water, or in the form of the glycerite or ointment, 
or some other fluid preparation may be preferred. The styptic collodion 
may also be employed for this purpose, the evaporation of the solvent 
leaving the surface covered with a thin layer of collodion impregnated 
with tannic acid. Tannic acid is used as a mouth wash in cases of swol- 
len gums, or relaxed throat, and may here be prescribed in a flavored 
solution or in the form of lozenges, of which the pharmacopoeia offers 
a choice. In certain forms of diarrhoea the astringent action of tannic 
acid is of considerable value, and occasionally when such drugs as 
ood-liver oil cause diarrhoea, tannic acid prevents this action without 
hindering their general effects. The pure drug is seldom used in these 
cases, as it is liable to derange the stomach and to form compounds 
with the albumins before it reaches the bowel, and catechu, krameria 
or kino is accordingly prescribed, either in the form of pills or in fluid 
preparations. Possibly all of these may be replaced in the early 
future by such artificial compounds as tannigen or tannalbin. Tannic 
acid stops hemorrhage by precipitating the proteids, when it comes 
into immediate contact with the bleeding point, but it is not of so 
much value for this purpose as some of the metallic astringents. 
When the bleeding point can be reached directly, the pure acid is used, 
but for hemorrhage of the intestine or stomach one of the extracts is 
preferred. Large enemata containing tannic acid have been advised 
in cholera, dysentery and similar conditions. 

In cases of poisoning with metals and alkaloids, tannic acid is often 
used to cause their precipitation in the stomach, but the tannate formed 
must be removed at once, as it is gradually dissolved in the digestive 
fluids. The administration of tannic acid is therefore only a tern- 



ANTHELMINTICS. 117 

porary expedient to allow of active measures being taken to empty the 
stomach. 

Some individuals are peculiarly susceptible to the action of tannic 
acid, which induces local irritation and inflammation wherever it is 
applied in these cases. 

Bibliography. 

Hennig. Arch. f. physiol. Heilkunde, xii., p. 599. 

Bosenstirn. Kossbach's Pharinakologische Untersuchungen, ii., p. 78. 

Lewin. Virchow's Archiv, lxxxi., p. 74. 

Stockman. Brit. Med. Journ., 1886, ii., p. 1077. Arch. f. exp. Path. u. Pharm., 
xl., p. 147. 

Morner. Ztschr. f. phys. Chem., xvi., p. 255. 

Heinz. Virchow's Arch., cxvi., p. 220. 

Schiitz. Arch. f. exp. Path. u. Pharm., xxvii., p. 202. 

Meyer. Deutsch. med. Woch., 1894, p. 626. 

Gottleib. Ibid., 1896, p. 163. 

Host. Arch. f. exp. Path. u. Pharm., xxxviii., p. 346. Centrabl. f. Physiol., xii., 
p. 258. 

Harnack. Zeitschr. f. physiolog. Chemie, xxiv., p. 115. 

Flatow. Deutsch. med. woch. Therap. Beilag., 1899, p. 37. 

Straub. Arch. f. exp. Path. u. Pharm., xlii., p. 1. 

Gebhart. Deutsch. Arch. f. klin. Med., lxvi., p. 585. 

IX. ANTHELMINTICS. 

Anthelmintics are drugs which are used to kill or remove intestinal 
worms. They possess no such mutual resemblances in their effects as 
are met with in the purgatives, and their arrangement in a class is 
therefore artificial ; at the same time, they have no marked affinities 
with other groups, and it is convenient to have those bodies which are 
used exclusively for this purpose placed together. 

In order to possess any value as an anthelmintic, a drug must, of 
course, act more strongly on the parasite than on the host, and this more 
intense effect may be attained either by a specific action on the para- 
site, or by the drug failing to be absorbed from the alimentary canal. 
As a matter of fact, the anthelmintics, with the possible exception of 
pelletierine, have no such specific action, and their use is rendered pos- 
sible only by their slow absorption. In this point they resemble the 
purgatives, from which they differ, however, in causing little or no 
irritation in the stomach or bowel. 

Anthelmintics are often divided into vermicides and vermifuges, 
according as they kill or merely cause the expulsion of the worm, but 
as this is determined largely by the quantity which comes in contact 
with the parasite and the rapidity with which the bowel is evacuated, 
the distinction is imaginary. 

Before the administration of an anthelmintic, the bowel ought to be 
emptied of its contents as far as possible by a light, easily digested 
diet and a laxative, and a brisk purge ought to follow some hours 
later, in order to remove the dead or stupefied worm. The anthel- 
mintic is often prescribed along with a purge. 

A number of drugs belonging to other groups are used occasionally 
as anthelmintics. Thus several of the volatile oils — tansy, turpentine - 



118 ORGANIC SUBSTANCES ACTING LOCALLY. 

have some reputation ; and chloroform is also administered occasionally 
by the mouth for its action on the parasites, but, like the volatile oils, 
is apt to produce gastric and intestinal irritation. The less easily 
absorbed antiseptics, such as naphthol, have been used with good 
results. Large enemata of salt solution, or of infusion of quassia, 
are thrown into the rectum when the worms infest the large intestines. 
The anthelmintics proper may be divided into those which are used for 
tapeworm, of which male fern, cusso and pomegranate are the most 
largely used, and those for the round worm of which santonin is the 
chief. Besides these, an enormous number of substances have been 
used popularly as anthelmintics, but have not been shown to have any 
advantages over those more generally adopted in medical practice. 



Male Fern (Aspidium Filix-mas). 

A number of ferns contain bodies which present considerable re- 
semblance to each other from a chemical as well as from a pharma- 
cological point of view, and which may therefore be classed together, 
at any rate until further information is available regarding them. The 
best known of these is the male fern (Aspidium Filix-mas). The active 
constituent of this remedy was supposed to be Filicic Acid by Poulsson, 
but Boehm has found a series of neutral and acid bodies present in 
much larger amount — Aspidin, Aspidinin, Flavaspidic Acid, Alba- 
spidin and Aspidinol — of which aspidin is contained in largest quantity 
in the root and is the most important, although aspidinin is also highly 
poisonous. A number of these constituents have been shown to be 
derivatives of phloroglucin, and it is probable that they are all closely 
related. The therapeutic and toxicological effects of the male fern 
are to be attributed then to aspidin, aspidinin and filicic acid. 1 

Action. — The extract or oleoresin of male fern, which is the only one 
of these plants used in regular medicine, as a general rule passes 
through the bowel without causing any symptoms whatever. The 
quantity of active substance dissolved, while sufficient to destroy the 
parasite, is too small to produce any effects on the host, and escapes 
with the other contents of the bowel, or if absorbed does not cause any 
symptoms. In some cases, however, where large quantities are admin- 
istered, or where some unknown conditions favor the absorption and 
retention of an unusually large amount of the active constituents, grave 
and even fatal symptoms may supervene. These consist in vomiting 
and purging, with acute pain in the abdomen, muscular weakness, 
confusion and somnolence, with occasional twitching of the muscles, or 
slight convulsive movements, collapse, coma and death. The stomach 

1 Nearly related bodies have been found in Aspidium athamanticum (Uncomocomo), 
which contains two forms of Pannic Acid, and in Aspidium spinulosum, while smaller 
quantities of acids occur in a large number of ferns. 

Several of these ferns enjoy a reputation as anthelminics for tapeworm, and their 
virtues are generally considered due to these bodies, although Robert maintains that 
it is partly to be ascribed to the fixed or volatile oils which accompany them. 



ANTHELMINTICS. 119 

and intestine are found congested and swollen, and sometimes covered 
with small ecchymoses. In some cases icterus has been observed to 
follow the administration of male fern, probably from the duodenal 
catarrh, but possibly from destruction of the red blood cells, the num- 
ber of which has been found to be diminished in some instances 
(Georgiewsky). In other cases permanent or temporary blindness lias 
been observed, without any distinct ophthalmoscopic appearances. 

In the rabbit, filicic acid produces very similar symptoms. The congestion 
of the stomach and intestine is evidently due to the local irritation produced 
by the poison, while the other symptoms point to changes induced in the 
central nervous system. It would seem probable that the spinal cord is 
affected in the same way as by strychnine, for the reflex excitability is dis- 
tinctly increased. The higher parts of the central nervous system seem to 
be depressed, and the paralysis of the respiratory centre is the cause of 
death, although the heart is also weakened by filicic acid. Inflammation of 
the kidney is said by some authors to occur, and in some cases Poulsson 
found evidence of glycuronic acid in the urine. 

In the frog, a mixture of depression and stimulation of the central 
nervous system is produced by filicic acid, along with a distinct diminution 
in the strength of the skeletal muscles and the heart. 

Aspidin injected into the frog causes dyspnoea followed by paralysis of the 
spontaneous and respiratory movements ; fibrillary twitching of the muscles 
sets in after some time and is succeeded by convulsive movements or tonic 
spasms, which indicate an increased activity of the reflexes of the spinal 
cord. The heart is depressed and eventually paralyzed, and the peripheral 
muscles are also weakened. The muscular tissue of the invertebrates is 
more powerfully affected by the constituents of male fern and Straub attributes 
its action on the tapeworm to its paralyzing muscle. Mammals do not seem 
to be affected by aspidin injected hypodermically or administered by the 
mouth, but when it is introduced directly into the blood vessels, it proves 
fatal by paralyzing the respiratory centre. Aspidinin induces very similar 
symptoms in the frog, while the other constituents are less active. 

The blindness which has been observed in some cases of male fern poison- 
ing has also been produced in dogs ; it occurs chiefly in young, weakly and 
anaemic individuals, and is due to the degeneration and atrophy of the 
ganglionic layer of the retina 

Pannic acid differs from filicic chiefly in its acting more strongly on muscle 
and less on the central nervous system of the frog. 

Preparations. 

Aspidium (UJS. P.), Male fern, the rhizome of Dryopteris Filix-mas and of 
Dryopteris marginalis, Filix Mas (B. P.), Male fern, the rhizome of Aspidium 
Filix-mas. 

Oleoresina Asptdii (U. S. P.), 2-8 c.c, (§-2 fl. drs.). 

Extr actum Filicis Liquidum (B. P.), 45-90 mins. 

The oleoresin (U. S. P.) and the liquid extract (B. P.) are practically iden- 
tical in composition. 

Therapeutic Uses. — Male fern is used exclusively in the treatment of 
tapeworm and of Anchylostomum duodenale. Previous to its admin- 
istration the bowel ought to be emptied, as far as possible, by a light 
diet for one or two days, and, where necessary, by a purgative. The 
oleoresin, or liquid extract, is then to be administered in the 1 form of 
pills or enclosed in a capsule or suspended in mucilage, and another 
purgative is required some 6-12 hours later. In case the parasite fails 



120 ORGANIC SUBSTANCES ACTING LOCALLY. 

to be dislodged, several days ought to be allowed to elapse before a 
second dose is given. Poulsson recommends that oily substances be 
avoided during the "cure," as they dissolve the filicic acid, and thus 
promote its absorption. It is impossible to estimate the importance 
of this fact since Boehm has discovered the other active constituents, 
but it is certainly suggestive that in many cases of poisoning with male 
fern castor oil had been given along with it or soon after. 

Bibliography. 

Poulsson. Arch. f. exp. Path. u. Pharm., xxix., p. 1 ; xxxv., p. 97 ; xli., p. 246. 

Robert. Therap. Monatsheft, 1893, p. 136. 

Birch- Hirsehf eld.. Graefe's Arch. f. Ophthalmologic, 1., p. 225. 

Georgiewsky. Ziegler's Beitriige, xxiv., p. 1. 

Boehm. Arch. f. exp. Path. u. Pharm., xxxv., p. 1 ; xxxviii., p. 35. 

Straub. Ibid., xlviii., p. 1. 

Walko. Deutsch. Arch. f. klin. Med., lxiii., p. 348. 

Cusso. 

Cusso, or Kousso, contains a neutral body, Kosotoxin, which is solu- 
ble in alcohol and in alkaline fluids, but is insoluble in water. Kosin, 
which was formerly supposed to be the active constituent, seems to be 
formed by the decomposition of kosotoxin, and is entirely inactive. 

Kosotoxin (C 26 H, 4 O 10 ) is probably nearly related to the active con- 
stituents of male fern, which it resembles somewhat in its pharma- 
cological action. 

Cusso has a bitter, somewhat astringent taste, and sometimes causes 
nausea and vomiting and some looseness of the bowels. In rare cases 
prostration and collapse, with irregularity of the pulse, are said to 
have occurred from its use. 

In the frog, kosotoxin paralyzes the nerve ends like curara, and has 
a specific action on the striped muscular tissue, which it weakens and 
eventually paralyzes. The heart muscle undergoes similar changes. In 
mammals the muscular action is well developed, but is accompanied by some 
stimulation of the medullary centres, indicated by rapid, dyspnceic breath- 
ing, salivation and vomiting. The stools are often fluid, and the urine is 
increased in amount. When it is injected directly into the circulation, some 
convulsive movements are often observed, and the heart is weakened and 
paralyzed. Kosotoxin seems to be a general protoplasm poison, as is indi- 
cated by its action on muscle, and by its retarding the growth of yeast. 

Preparations. 

Cusso (U. S. P., B. P.) (Kousso or Brayera), the female inflorescence of 
Hagenia Abyssinica (Brayera anthelmintica). 

Extractum Cusso Fluidum (U. S. P.), 15 c.c. (J fl. oz.). 

Cusso is generally given by suspending 15 G. (h oz.) of the powdered 
flowers in water, or the fluid extract may be prescribed, although it is said 
to be less certain in its effects. Kosotoxin has not yet been prescribed for 
therapeutic purposes. The usual preliminary treatment ought to be insti- 
tuted, but no purge is required after Cusso as a general rule. 

Therapeutic Uses. — Cusso is used exclusively as an anthelmintic in 
cases of tapeworm. 

Bibliography. 

Leichsenring. Arch. d. Pharm., ccxxxii., p. 50. 
Handmann. Arch. f. exp. Path. u. Pharm., xxxvi., p. 138. 



ANTHELMINTICS. ] 2 1 

Granatum. 

The bark of the pomegranate contains a very large amount of tannic 
acid (20-25 per cent), along with numerous alkaloids, of which 
Pelletierine, or Punicine, and Isopelletierine alone are active in ordinary 
doses. All the pomegranate alkaloids are closely related chemically 
to each other and to tropine (see atropine). None of them can be 
classed among the more active poisons as far as man and the higher 
animals are concerned. 

In man, large doses cause heaviness, confusion, giddiness and very 
marked weakness of the limbs. The consciousness is but little affected, 
but the sight is often dim and uncertain, and in one case complete 
blindness persisted for several days. Occasionally nausea and discom- 
fort in the abdomen are complained of, and more rarely vomiting, 
tremors and cramps of the leg muscles are produced ; the gastric symp- 
toms are perhaps due to the large quantity of tannic acid in the drug 
rather than to the alkaloids. 

In the frog and in most mammals, pelletierine causes a distinct increase in 
the reflex irritability of the spinal cord and medulla oblongata, along with 
some depression of the higher divisions of the central nervous system. The 
muscles of the frog are affected in much the same way as by veratrine, and 
very large doses weaken or paralyze the conductivity of the nerve plates 
like curara. The heart muscle is also acted on and its pulsations are slowed 
in the frog, although they may be temporarily augmented in force. 

Pelletierine and isopelletierine have a specific action on tapeworms, 
for Schroeder found that a solution of one part in 10,000 was suffi- 
cient to kill them in ten minutes, while a stronger solution had prac- 
tically no effect upon other intestinal worms. 

Preparations. 

Granatum (U. S. P.), Granati Cortex (B. P.), Pomegranate bark, the bark 
of the stem and root of Punica Granatum. 

Decoctum Granati Corticis (B. P.), \-2 fl. oz. 

Granatum is used as a decoction formed of 30-60 G. (1-2 oz.) in 250 c.c. 
of water {\ pt.), to be taken in two parts, at an interval of one hour. The 
bark ought to be as fresh as possible, as the alkaloids decompose on keep- 
ing. The presence of large quantities of tannic acid renders the decoction 
very unpleasant to the taste, and flavoring substances are therefore gener- 
ally prescribed with it, or, to avoid the tannic acid effects, pelletierine may 
be prescribed in doses of 0.1-0 5 G. (2-8 grs.). The pelletierine of com- 
merce is often a mixture of all the alkaloids and has therefore to be given 
in larger doses. It is well to prescribe it along with four times its weight of 
tannic acid, in order to prevent its absorption in the stomach. Pelletierine 
tamiate is given in doses of 0.75-1.5 G. (10-20 grs.). 

Therapeutic Uses. — Granatum is used exclusively as an anthelmintic. 
The preliminary treatment is the same as that given under aspidium, 
and a purge ought to be given J-2 hours after the decoction. 

Bibliography. 

Dujardin-Beaumetz. Bull, de Therap., xeviii., p. 433. 

Berenger-Feraud. Ibid., xcvii., pp. 8, 337, 391. 

v. Schroeder. Arch. f. exp. Path. u. Pharm., xviii., p. 381, and xix., j>. 290. 



122 ORGANIC SUBSTANCES ACTING LOCALLY. 

Kamala (U. S. P.) is a reddish-brown powder which consists of the minute 
glands and hairs obtained from the surface of the fruits of Mallotus Philip- 
pensis. It contains two or more substances which have been termed Kamalin, 
Eottlerin or Mallotoxin, and which are probably neutral bodies like kosotoxin, 
but it is not known which of these is the active constituent. Kamala is used 
in cases of tapeworm in doses of 2-8 G. (30 grs.-\ oz.) suspended in water. 
It acts as an intestinal irritant, causing purging and more rarely nausea and 
vomiting. No purge is necessary, therefore, after the powder. An alco- 
holic tincture of kamala has been found quite as efficient as the powder. 

Pepo (pumpkin seed) contains a fixed oil and resin, and the latter seems 
to have considerable power as an anthelmintic, although this is disputed 
by some authorities. No symptoms are produced by very large quantities of 
the powdered seeds. 

Pepo (U. S. P.), the seed of Cucurbita pepo, Pumpkin seed, is generally 
administered in doses of 60-120 G. (2-4 oz.), the powdered seed being sus- 
pended in an emulsion or in sugar or honey. Pumpkin seed has no laxa- 
tive effect and its administration is, therefore, to be followed by a purge. 
The resin has been used with good effects in some cases. 

Santonin. 

Santonin (C 15 H lg 3 ) is an anhydride or lactone of santoninic acid, 
which is formed from it by the action of alkalies, and is a derivative of 
naphtalene. It occurs in Artemisia maritima along with a nearly related 
body (artemisin) and a volatile oil (cineol). Santonin is very insoluble 
in water, but is dissolved by alkalies, with which it forms santoninates. 

Action. — Owing to its insolubility in water, santonin has only a 
slightly bitter taste in the mouth. It is partially dissolved in the 
stomach and absorbed, but enough passes into the bowel to effect the 
removal of some forms of intestinal worms. Under special conditions 
it is possible that the greater part of the santonin may be absorbed in 
the stomach, however, and general poisoning results without the para- 
sites being affected. A certain amount of absorption occurs in every 
case, as is shown by the disorders of color vision and by the yellow 
coloration of the urine. At first objects appear of a bluish color to 
the patient, but this aberration is of comparatively short duration and 
may in fact pass unnoticed. It is followed by a much longer period of 
" yellow sight " or xanthopsia, during which objects that are brightly 
illuminated seem to have a yellow tinge, blue seems green, and violet 
is indistinct, although in dimmer lights the violet may still predomi- 
nate. In severe poisoning the appreciation of the darker colors becomes 
very imperfect, and violet and even blue may fail to be distinguished 
from black. In general the violet end of the spectrum is shortened, 
while the yellow impresses the retina more vividly than normally. 
Sometimes " hallucinations " of vision are said to occur under santonin, 
although these seem to be unimportant ; thus one observer saw green 
globes on a violet background whenever he closed his eyes. These 
aberrations of sight are the most generally observed symptoms produced 
by santonin, but in some cases the sense of taste and smell, and more 
rarely the hearing, are also deranged. These symptoms all pass off in 
the course of a few hours, a second stage of " violet sight " occasionally 
intervening before complete recovery. 






ANTHELMINTICS. 1 23 

The symptoms produced by the absorption of large quantities of 
santonin are so uniform in man and the other mammals that it is suffi- 
cient to enumerate those observed in experiments on the dog. The 
first distinct effects are generally twitching of the muscles of the 
head, frequently beginning on one side. These are followed by roll- 
ing of the eyes, grinding of the teeth, flexion and extension of the 
neck and rotation of the head from side to side, later by regular epi- 
leptiform convulsions in which the animal is first thrown into opistho- 
tonos and then into clonic spasms of the limbs and trunk. These 
are interrupted by intervals of repose during which a curious momen- 
tary contraction of all the muscles of the body is often noticed. Dur- 
ing the convulsive seizures the respiration is irregular and insufficient, 
and in fatal cases it fails to return after the convulsion passes off, and 
the animal dies of asphyxia. In man, some confusion, nausea and 
vomiting occasionally occur after quantities which are too small to 
produce convulsions, and in several cases aphasia has been observed. 
In frogs, convulsions are produced by santonin as in mammals, but 
they are preceded by a prolonged stage of depression, which is entirely 
absent in the higher animals. 

These symptoms manifestly point to changes in the central nervous 
system. The xanthopsia is generally referred to a specific action on 
the retina, though some hold that the central apparatus of vision in 
the brain is the seat of the action. 1 The condition has been ascribed 
to a preliminary stimulation and subsequent depression of the sense 
organs for the perception of the violet and eventually of the blue rays 
of the spectrum, or more precisely to some obstruction to the regener- 
ation of the substance in the retina which normally appreciates violet 
rays (Filehne). The clonic nature of the convulsions at once points 
to an affection of the brain rather than of the cord, but some dis- 
cussion has arisen as to how far the cortical areas are involved and 
how far the symptoms may be explained by stimulation of the basal 
ganglia. The latest investigators have come to the conclusion that the 
epileptiform convulsions are due for the main part to the stimulation 
of the cortex, while the sudden contractions observed in the intervals 
of repose are ascribed to increased activity of the parts lying between 
the cerebral peduncles and the medulla oblongata. The gray matter 
of this division of the central nervous system also seems involved in 
the clonic movements, although these are only elicited in their full 
strength through action on the cerebral cortex (Kramer). 

Although these parts of the central nervous system are the most 
susceptible to the action of santonin, large quantities also affect the 
cord after division of the medulla oblongata and produce tonic con- 
vulsions resembling those seen in strychnine poisoning. 

The medullary centres seem to be comparatively little affected by 
santonin, the respiration being interfered with during the spasms, but 
returning to its ordinary rate and strength during the intervals. The 

1 The view formerly held that the yellow vision was due to a yellow pigmentation of 
the vitreous humor or the retina is undoubtedly erroneous. 



124 ORGANIC SUBSTANCES ACTING LOCALLY. 

circulation is altered only by the asphyxia, and the heart continues to 
beat long after the respiration has ceased. 

Santonin undergoes some oxidation in the tissues and is excreted in 
the faeces and urine in several forms, two of which have been exam- 
ined by Jaffe and found to be oxysantonins. The urine and some- 
times the faeces have a deep yellow color, which changes to red or 
purple when alkalies are added. A similar reaction is obtained from 
the urine after the administration of chrysophanic acid, as in rhubarb 
or senna, and a number of reactions are given to distinguish between 
these two pigments, which, however, it can scarcely be necessary to do 
frequently. 

Thus the red of chrysophanic acid is permanent, while that of the san- 
tonin pigment fades after a time, and reducing agents, such as zinc, remove 
the former, and not the latter, while barium and calcium precipitate the 
chrysophanic and not the santonin pigment. 

Santonin was formerly credited with some cholagogueand diuretic action, 
but more accurate investigations have shown that it has no such effects. 

According to Harnack and Hochheim, santonin lowers the temperature in 
most animals by increasing the loss of heat through dilation of the cuta- 
neous vessels ; it resembles in this respect several other convulsive poisons 
investigated by these authors. 

Santonin is universally used as a remedy for the round worm, As- 
caris lumbricoides, and most clinicians believe that it has a specific poi- 
sonous action on these animals, and that its undoubted effects are due 
to its killing them. In experiments on the entozoa outside the body, 
however, von Schroeder found that santonin solutions were by no 
means fatal to them, and he explains their therapeutic effects by sup- 
posing that santonin renders the intestine so unpleasant an abode 
for the parasites that they migrate from it voluntarily into the large 
bowel, and are carried out by the purgative. Another explanation is 
that the ascarides are stimulated to active movements or convulsions, and 
are then hurried through the intestine by its peristaltic contractions, 
while the latest investigator supposes that the santonin is dissolved by 
the gastric juice and is then precipitated in a state of fine division, in 
which he believes that it is much more fatal to the parasites than 
when in solution. Von Schroeder's explanation is the one most widely 
received. The worms are often found in active movement when passed 
after santonin, although this movement ceases very soon afterwards 
from the exposure to cold. 

The alkaline salts of santoninic acid act in precisely the same way as san- 
tonin itself, but are less suitable as anthelmintics owing to their greater 
solubility and rapid absorption. 

A number of santonin derivatives have been examined by Coppola, who 
found that many of them produced effects which were practically identical 
with those of santonin, while in others the stage of convulsions was preceded 
by one of depression. Santoninoxin, a compound of santonin and hydroxy 
lamin, and calcium santoninate have been proposed as substitutes for san- 
tonin in therapeutics, but have not received much attention as yet. 






ANTHELMINTICS. 1 25 

Pkeparatioss. 

Santonica (U. S. P.), Levant wormseed, the unexpanded flower-heads of 
Artemisia pauciflora. 

Santoninum (U. S. P., B. P.), C 15 H 18 3 , a neutral principle derived from 
Santonica. Santonin is colorless when freshly prepared, but assumes a yel- 
low color when exposed to the light. This does not seem to impair its 
activity materially, but it is preferable to avoid it by keeping santonin in 
amber- colored vials. Dose, 0.03-0.1 G. (£-2 grs.). 

Trochisci Santonini, each containing 0.03G. (\ gr.) of santonin, U. S. P.; 
each containing 1 gr., B. P. 

Therapeutic Uses. — Santonin is used almost exclusively to remove 
Ascaris lumbricoides from the intestine. It is much less effective against 
tapeworm or other intestinal parasites. The lozenges are generally 
prescribed, one for children, two for adults, U. S. P., while the dose of 
the B. P. lozenge is one for an adult. Lewin recommends the admin- 
istration of santonin in oily solutions, especially in castor oil, as less is 
absorbed from the stomach than when it is prescribed in other ways. 
The bowel ought to be emptied by suitable diet and a laxative before 
the santonin is administered, and a sharp purge ought to be given 2-4 
hours afterwards in order to bring away the entozoa. 

Santonin has been advised in some retinal diseases, but the results 
have generally been unsatisfactory. 

Poisoning. — In cases of poisoning, the stomach and bowel ought to 
be evacuated as rapidly as possible by the use of emetics or of the stom- 
ach tube, and of purgatives. The convulsions may be controlled by 
the use of chloroform or ether. The xanthopsia requires no treat- 
ment, and is not to be regarded as heralding any dangerous develop- 
ments, as it occurs to some degree in the great majority of cases in 
which santonin is administered. 

Bibliography. 

Binz. Arch. f. exp. Path. u. Pharm., vi., p. 300. 

Lewin. Berl. klin. Woch., 1883, p. 170. 

Luchsinger. Pfliiger's Arch., xxxiv., p. 293. 

Jaffe. Ztschr. f. klin. Med., xvii. Suppl., p. 7. Ztsch. f. phvs. Chem. , xxii., p. 538. 

Falck. Deutsche Klinik, 1860, p. 257. 

Kramer. Ztschr. f. Heilkunde, xiv., p. 303. 

Turtschaninoic. Arch. f. exp. Path. u. Pharm., xxxiv., p. 208. 

v. Schroder. Ibid., xix., p. 290. 

Monaco. Arch, ltalien., xxvi., p. 216. 

Harnack. Zts. f. klin. Med., xxv., p. 16; Arch. f. exp. Path. a. Pharm., xlvi., 
pp. 272, 447. 

Rose. Yirchow's Arch., xvi., p. 233; xviii., p. 15; xix., p. 522; xx., p. 245; 
xxviii., p. 30. 

Hiifner. Arch. f. Ophthalmol., xiii., p. 309. 

Preyer. Pfliiger's Arch., i., p. 299. 

Coppola. Maly's Jahresberieht, xvii., p. 92. 

Filehne. Pfliiger's Arch., lxxx., p. 96. 

Spigelia. 

Another remedy used in cases of round worm is pink root, Spigelia mari- 
tima (U. S. P.), the active principle of which is unknown, although an 
alkaloid, spigeline, is said to occur in it. Occasional cases of poisoning have 



126 ORGANIC SUBSTANCES ACTING LOCALLY. • 

been observed, especially in children, the symptoms consisting in flushing 
.and dryness of the skin, often with some cedematous swelling of the face, 
delirium and sopor followed by dimness of sight or temporary blindness. 
In frogs spigelia appears to depress the brain and spinal cord, and the heart 
beats more slowly and weakly, while in rabbits the most prominent symp- 
toms arise from the breathing, which becomes slow and labored and finally 
ceases in a convulsive attack. In the dog and cat its injection is followed 
by vomiting, great weakness and incoordination of the movements, restless- 
ness, rapid dyspnceic respiration and finally by stupor, coma and death from 
failure of the respiratory centre. 

Spigelia (U. S. P.), the rhizome and roots of Spigelia maritima. 

Extractum Spigelian Fluidum (U. S. P.), 4-8 c.c. (1-2 fl. drs.). 

The fluid extract is used to remove round worms, which it seems to effect 
in very much the same way as santonin. It ought to be preceded and fol- 
lowed by a purge. 

One of the volatile oil series which is frequently used as an anthelmintic 
is that obtained from Chenopodium ambrosioides or American worm-seed. 

Chenopodium (U. S. P.), American Wormseed, the fruit of Chenopodium 
ambrosioides, var. anthelminticum. 

Oleum Chenopodii (U. S. P.), 0.2-0.3 c.c. (3-5 mins.). The oil is admin- 
istered on sugar or in an emulsion. 



PART II. 

ORGANIC SUBSTANCES CHARACTERIZED 

CHIEFLY BY THEIR ACTION AFTER 

ABSORPTION. 

I. NARCOTICS OF THE METHANE SERIES. 
ALCOHOL-CHLOROFORM GROUP. 

A large number of the derivatives of the methane series are 
characterized by the production of depression of the central nervous 
system, more especially of the cerebrum, and some of them are per- 
haps the most extensively employed of all drugs. With the exception 
of alcohol, which has been known since prehistoric times, the use of 
the members of this series scarcely extends over more than half a 
century. 

From the large number of substances belonging to this division of 
organic chemistry which are possessed of narcotic powers, it would seem 
that the combination of carbon and hydrogen in the form characteristic 
of this series is possessed of a special relation to the protoplasm of 
the nerve cells, or in other words, carbon radicles combined in open 
chain form are possessed of specific depressant powers. As a general 
rule the greater the number of these radicles contained in the chain, 
the more powerful the action, provided the substance is not changed 
so as to become incapable of absorption. Thus, in the alcohol series 
a regularly ascending scale of toxicity is met, commencing with methyl 
and passing through ethyl, propyl, butyl and amyl alcohols, of which 
each succeeding member is more poisonous than its predecessor. The 
later members of the series, however, become less soluble in the body 
fluids, are less easily absorbed and therefore less toxic. 

The toxicity of these bodies may also be reduced or removed completely by 
the presence of acid-forming groups. Thus ethyl alcohol (CH 3 — CH.,OH) 
is a powerful depressant, but propionic acid (CH 3 — CH 2 — COOH) is entirely 
inactive in this direction. Again, one hydroxyl group in a substance does 
not remove its narcotic action, while two hydroxyls reduce it very consider- 
ably or may destroy it entirely ; thus ethvl alcohol (CH 3 — CH.,011) is prob- 
ably quite as active as ethane (CH— CEQ, but glycol (CH,OH— CHOlh is 
almost inactive. A still more striking example of the effects of several 
hydroxyl groups is seen in the comparison of propvl alcohol (CI I.. — CH, 
— CH 2 OH) with glycerin (CH 2 OH— CHOH-CH,OH), the former being a 
powerful depressant, while the latter is practically devoid of any such action 
on the central nervous system. Compounds of the fatty series may also lose 
their characteristic effects by their combination with more active radicles. 
Thus ethane (C 2 H 6 ) is a member of the narcotic series, but ethyl nitrite 

127 



128 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

(C 2 H 5 — NO) cannot be classed with it, because the — O — NO group has a 
very powerful and entirely different effect ; very small quantities of ethyl 
nitrite are required to produce the nitrite effect, so that the depressant action 
is pushed into the background. Members of the methane series often lose 
their depressant action when combined with nitrogen so as to form substi- 
tuted ammonia. Thus trimethylamine (N(CH 3 ) 3 ) has no depressant action, 
although each of the methyl radicles alone would possess it. Again, the sub- 
stitution of a member of the aromatic series for one of the fatty substances 
sometimes changes the action from that characteristic of the alcohol-chloro- 
form group to that of the benzol series. For example, ether (C 2 H 5 — O — C 2 H 5 ) 
is one of the most valuable anaesthetics, but if one ethyl radicle be substi- 
tuted by phenyl (C 6 H 5 — O — C 2 H 5 ), it loses this property entirely. Others, 
however, retain their depressant action, as, for example, acetophenone 
(C 6 H-CO-CH 3 ). 

A very interesting hypothesis has recently been suggested by Meyer ' 
and Overton 2 to explain why so many of the bodies of this series act 
as narcotics. Practically all of them are more soluble in lecithin and 
cholesterin than ki water and accordingly when they reach the blood 
they tend to accumulate in the nerve cells, which are rich in cholesterin 
and lecithin. Here they may be supposed to partially dissolve these 
constituents, or, at any rate, to change their relations to the rest of the 
nerve cells and this derangement of their normal condition leads to 
impairment of the function of these cells, or narcosis. But many other 
substances (e. g., many of the benzol derivatives) possess these physical 
properties equally with the members of the methane series, and yet 
induce no narcosis proper, so that though the physical characters of 
these drugs may probably be important factors in their action, they 
cannot be held to determine it solely. 

It is impossible to enumerate here all the substances of this series 
which possess more or less depressant action on the nerve centres. A 
very large number of them have been the subject of investigation, but 
only a few of them have become established remedies. 

Among the hydrocarbons the fifth, Pentane, and the eighth, Octane, have 
been proposed as anaesthetics for short operations, but have never received 
an extensive trial. Some of the unsaturated hydrocarbons have also been 
suggested, such as Amylene, which was introduced by Snow, but was found 
to vary exceedingly in its properties, and proved to be a mixture of several 
isomers. One of these has lately been isolated and recommended for short 
operations under the name of Pental ( (CH 3 ) 2 = C = CH — CH 3 ). Another 
unsaturated hydrocarbon which has been shown to possess narcotic proper- 
ties is Acetylene, but its action on the heart is said to preclude its use in 
practical therapeutics. 

Among the alcohols, Ethyl alcohol (C 2 H.HO) stands preeminent from its 
extensive use in therapeutics as well as from its importance in dietetics and 
as a poison. Other alcohols, however, have been found to resemble it in 
action. Thus Methyl alcohol is weaker, while Propyl and Butyl alcohols 
are stronger, but the symptoms produced by each are practically identical. 
The only other alcohol that has been introduced into therapeutics is Amy- 
lene hydrate, or tertiary isoamyl alcohol ( (CH 3 ) 2 C(OH)CH 2 CH 3 ), which has 
been recommended as a hypnotic. 

1 Arch. f. exp. Path. u. Pharm., xlii., p. 109 and xlvi., p. 338. 
2 Studienu. d. Narkose. Jena, 1901. 



NARCOTICS OF THE METHANE SERIES. 129 

The ethers contain one very important member in Ethyl ether ((C HJO) 
which is perhaps the best anaesthetic in use. 

The aldehydes possess narcotic properties, but ordinarily are irritant and 
of disagreeable odor, so that they have not been used in therapeutics. 1 Par- 
aldehyde (C 6 H 12 3 ), a polymer of ordinary aldehyde, is, however, one of the 
newer hypnotics. Several derivatives of the aldehydes have been in- 
troduced, such as Methylal (HCH(OCH 3 ),) and Acetal (CH 3 CH(OC,H.),). 
Another important aldehyde derivative is Sulphonal ( (CH 3 ) 2 ClSO,C 2 H,) ) 
which has received considerable attention of late years as a hypnotic. Two 
analogous compounds, Trional and Tetronal, in the first of which one in 
the second both methyl groups are replaced by ethyl, are said to be more 
powerful than sulphonal. 

The only member of the ketones which has received attention at the hands 
of therapeutists, is Hypnone (C 6 H 5 COCH 3 ), which has been used as a hyp- 
notic. 

The esters, or ethereal salts, have been but little used as depressants, and 
seem to be much weaker in action than the corresponding ethers.- Some of 
them, as amyl nitrite, owe their use not to the action of the alkyl radicle, but 
to the acid with which it is compounded, and are therefore included in 
another group. One ester which has been used as a narcotic in therapeutics. 
and to a much greater extent in animal experiments, is Urethane, the ethyl 
ester of carbamic acid (CO(NH,)(OC,H 5 )). An analogous compound recently 
recommended as a hypnotic is Hedonal (CO(NH 2 )(OC 5 H n )), the carbamic ester 
of tertiary amyl alcohol. 

The acids of the methane series possess little narcotic action as a general 
rule, and have not been used in therapeutics for this purpose, though butyric 
acid is said to have distinctly depressant effects on the central nervous 
system. When hydrogen atoms of these acids are replaced by chlorine or 
bromine, they acquire a much stronger action ; thus acetic acid is practically 
devoid of narcotic action, while some of the chloracetic and bromacetic acids 
are narcotic. But their effects on the other organs of the body preclude their 
use in therapeutics 3 

Some of the most important members of this series are halogen substitution 
products, formed by replacing one or more atoms of hydrogen in the simpler 
substances of the fatty series by chlorine. This substitution often increases 
the narcotic power to a very great extent : methane (CH 4 ) is practically 
not depressant, but if one, two or three of the hydrogen atoms in the mole- 
cule be substituted by chlorine, forming CH 3 C1, CH.,C1 2 and CHC1 3 , the nar- 
cotic power increases with each CI added. The best known of these is 
Chloroform (CHC1 3 ), which is the most powerful anaesthetic in use. Other 
analogous compounds have also been emploved as anaesthetics, as Ethylene 
Chloride (CH 2 C1— CH 2 C1) and Ethylidine Chloride (CH 3 — CHC1 2 ), but these 
have fallen into disuse. Another important substitution product is Chloral, 
or chloral hydrate (CC1 3 CH(0H) 2 ), which is the hydrate of trichloraldehyde 
(CCl 3 CHO). Another analogous compound used occasionally is Butyl 
chloral, or Croton chloral (C 3 H 4 01 3 CH(OH) 2 ), and a very recent addition to 
the ffroup is Chloretone or Aneson (trichlorpseudobutvlalcohol or acetone- 
chloroform, CC1 3 C(CH 3 ) 2 0H). 

Several compounds of chloral have been recently introduced into thera- 
peutics, such as Chloralamide (CCl 3 CHOH — XHOHO). which is a combina- 
tion of chloral with formamide, and Chloralose (C 8 H U C1 3 6 ), a compound of 
chloral and grape sugar. 

It has already been mentioned that the substitution of chlorine for hydro- 
gen in the acids endows them with a narcotic effect. Another example o\' 

1 Formaldehyde is used as a disinfectant. (See Formalin. ) 

2 Vogel, Pniiger's Arch., lxvii., p. 141. 

8 Mm/er, Arch. f. exp. Path. u. Pliarm., xxi., pp. 97, 119. Po/il, ibid., wiv., 
p. 112.' 
9 



130 ORGANIC DRUGS ACTING AFTER ABSORPTION 

the alteration of the properties of a substance by the substitution of chlorine 
for hydrogen is offered by glycerin, which in itself inert, becomes depressant 
to the central nervous system when its hydroxyl radicles are replaced by 
chlorine. 1 

Some attempt has been made to introduce bromine instead of chlorine into 
the methane derivatives, because bromides are central nervous depressants, 
and it was hoped that a combination of the methane and the bromide effects 
could be thus obtained. But, as will be explained, the bromides owe their 
action to the bromide ion, which is not present in these organic compounds. 
Ethyl bromide (C 2 H 5 Br) has been used as an anaesthetic, and Bromoform 
(CHBr 3 ) as a narcotic, but only to a limited extent. The analogous com- 
pounds formed with iodine possess a powerful action which is different from 
that of the other methane derivatives, and which precludes their use as nar- 
cotics. (See Iodoform.) 

The augmented effect of these halogen substitution derivatives has been 
explained by reference to a supposed depressant effect of chlorine and bro- 
mine upon the brain. But even though this were proved to be the case, it 
would not elucidate the matter, for chlorine is not set at liberty in the 
tissues when chloroform is inhaled, the molecule acting as a whole. (See 
page 24.) 

The chlorine and bromine derivatives of methane are not only more power- 
ful drugs, but also more powerful poisons than the ordinary compounds : 
much less chloroform is required to anaesthetize than methane, but much 
less is required to kill. In addition, these compounds, especially those con- 
taining chlorine, seem to have a more powerful action on the heart and cir- 
culation and on the metabolism than the others. In other words, the chlo- 
rine bodies have a wider field of activity and are more nearly general 
protoplasm poisons. (See Chloroform.) 

All of the narcotics of the methane series resemble each other closely 
in their general action. This consists of a first stage of imperfect con- 
sciousness and confused ideas, followed by one of wild excitement, and 
eventually by complete unconsciousness, which may terminate in death. 
The second stage is much more marked after some of the series than 
after others, and is often entirely absent. It has given rise to the 
theory that these drugs stimulate the nerve cells before paralyzing 
them, but an alternative explanation is that the functions of control 
and inhibition are lessened, and the centres of motion are thus left free 
and act more strongly than normally. This question has been most 
discussed in regard to alcohol, and will receive greater attention under 
that heading. (See pages 133-135.) 

The depression of the central nervous system induced by these 
bodies is in the majority of cases accompanied by an alteration of the 
circulation of the brain in the direction of congestion or anaemia, and 
it was formerly believed that these drugs induced depression by caus- 
ing anaemia of the brain and thus starving the nerve cells. But this 
improbable explanation has been refuted by experiments in which all 
the blood of a frog was replaced by salt solution, and the brain cells 
thus deprived of nutrition before an anaesthetic was applied ; chloro- 
form then induced the same changes as in normal animals. There is 
no question at the present time that these bodies act directly on the 

1 Marshall and Heath, Journ. of Physiol., xxii., p. 38, and Kionka, Arch, internat. 
de Pharmacodyn., vii., p. 475, give a resume of the relation of the chlorine substi- 
tutes to the simple methane derivatives. 



ALCOHOL. 131 

nerve cells, or rather on the central part of the neurons. Binz sug- 
gested that the change was of the nature of a coagulation of the 
protoplasm, but this theory is not supported by microscopic investiga- 
tion, and more recently histologists have been inclined to regard the ef- 
fects of the central nervous depressants as associated with alterations 
in the distribution of the chromatin in the nerve cells. A simple 
explanation of nervous depression has been suggested in the retraction 
of the dendrites. These finer processes of the nerve cells are supposed 
to serve to maintain the connection between the individual cells during 
consciousness by forming ramifications between them, while it is sug- 
gested that in natural sleep and in unconsciousness in general, the den- 
drites are withdrawn, and the cells are thus cut off from intercom- 
munication. Some changes which have been observed in the dendrites 
after narcotics might be explained in this way, but the explanation is 
only a hypothesis at present. There is, however, every probability 
that the nerve cell depressed by drugs undergoes changes similar to 
those of natural sleep and the changes in the brain circulation (anaemia) 
may be regarded as the result and not as the cause of the depression 
in both conditions. 

While the members of this group resemble each other closely in their 
effects on the central nervous system, they are used for very different 
purposes in therapeutics and may therefore be discussed in three sub- 
groups : 1, alcohol ; 2, general anaesthetics, and 3, narcotics or hyp- 
notics. It must be recognized, however, that there is no hard and fast 
line dividing these subgroups ; for the anaesthetics, chloroform and 
ether, may be used in small quantities to produce rest and sleep, and 
would then, strictly speaking, be narcotics ; while, on the other hand, 
chloral and sulphonal, which are generally used as hypnotics, give rise 
to complete anesthesia when administered in large quantities. 

I. Alcohol. 

Ethyl alcohol (CH 3 CH 2 OH) has been known in an impure form 
since the earliest times, and as far back as the history of medicine ex- 
tends, has been used as a drug. Its medicinal reputation has under- 
gone many fluctuations, by many held to be a panacea, by others it 
has been considered of little or no value as a remedy, but of the 
greatest importance as a poison. 

Alcoholic liquors are generally prepared by the fermentation of 
sugars, which either exist preformed in the fruits, or are derived from 
starch by a preliminary ferment action. The simple liquors (wines and 
beers) generally contain only a low percentage of alcohol (2—20 per 
cent.), and the stronger preparations (spirits) are prepared from them 
by distillation, which raises the percentage to 30—60 per cent, and a! 
the same time removes the non-volatile constituents. Spirits and 
liquors are not, however, simple mixtures of alcohol and water hut 
contain many other volatile substances, the character of which is little 
known, and which are called oenanthic ethers. Some of them have 



132 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

been shown to be higher members of the alcoholic series, while others 
would seem to be of entirely different constitution. The name is de- 
rived from their giving the odor and taste, or bouquet, to wines. 

Pure alcohol is obtained from these spirits by repeated distillation 
and by special measures designed to remove the water. It is seldom 
used in medicine, some form of spirits, wine, or beer being prescribed 
instead. 

Action. — The value of alcohol in medicine depends upon three chief 
points : 1, its irritant local action ; 2, its action on the central nervous 
system, and 3, its value as a food. 

The irritant action is not so marked as that of many other substances, 
but is of much greater importance, owing to the habitual use of this 
drug. It is probably due at any rate in part to the withdrawal of 
water from the cells and is shown by the results of its application to 
the skin, to wounds and to the mucous membranes. Applied to the 
skin in sufficient concentration (e. g., 60-90 per cent.), it produces red- 
ness, itching and a feeling of heat like other volatile and irritant sub- 
stances, such as the volatile oils. Alcohol is, however, much less 
irritant and at the same time more volatile than these, so that unless 
its evaporation be prevented, it may produce a sensation of cold and 
have little or no irritant action ; this is especially the case when dilute 
alcohol is used, no very distinct appearances of irritation of the skin 
being produced by solutions under 40-50 per cent. In ulcers and 
other unprotected surfaces, the irritant action is much greater and the 
cell division is accelerated, so that, judiciously applied, it may quicken 
the healing of such breaches of continuity. Concentrated solutions, 
however, cause a precipitation of the albumins, and act first as astrin- 
gents and later as corrosives, until they are diluted by the fluids of the 
wound. 

Its effects on mucous membranes are similar to those on wounds. 
In the mouth strong alcohol produces a burning, unpleasant sensation 
which passes to the throat and stomach when it is swallowed, and if the 
concentrated vapor be inhaled, it causes irritation and reflex closure of 
the glottis. The effects of alcohol on the digestive functions are so 
important that they will receive further attention (page 140). 

The action of alcohol on the Nervous Centres, differs a good deal in 
individuals. In small quantities it generally produces a feeling of 
well-being and good-fellowship, along with increased confidence in the 
powers, mental and physical, of the subject of the experiment. Larger 
quantities are followed by a certain amount of excitement, marked by 
laughter, loquacity and gesticulation. The face becomes flushed and 
hot, the eyes brighter and livelier, the pulse is accelerated. Even at 
this stage self-control is partially lost and the will power is weakened. 
The speech may be brilliant, but it often betrays the speaker ; the 
movements are more lively, but they are often undignified. The loss 
of self-control is often indicated further by furious outbursts of anger 
and unreasonableness, or by the indulgence in maudlin sentimentality 
and sensual fancies. The sense of responsibility and the power of 






ALCOHOL. 133 

discrimination between the trivial and the important are lost, and 
the individual has no regard for the feelings of others or the ordi- 
nary conventions of life. If the bout be further continued, the 
movements become uncertain, the speech becomes difficult and stam- 
mering, the walk becomes a stagger, and a torpid slumber follows. 
Often nausea and vomiting set in, although these are entirely absent 
in some cases. On awaking from slumber, very great depression is 
generally suffered from, together with nausea and vomiting, and want 
of appetite, which may last for several days and is associated with all 
the symptoms of acute gastric catarrh. 

Very large quantities of alcohol lead to a deep, torpid sleep, which 
eventually passes into total unconsciousness, resembling the condition 
in chloroform anaesthesia ; the respiration becomes stertorous and 
slow, and the face, which has hitherto been flushed, becomes pale or 
cyanotic. This condition may last for several hours and end in death 
from failure of the respiration, but in other cases the anaesthesia be- 
comes less deep, and after a very prolonged sleep the patient recovers. 
When the stage of anaesthesia is reached, it lasts very much longer 
than that produced by chloroform and ether. It is said that persons 
rarely or never recover if unconsciousness lasts longer than 10-12 
hours after the drinking bout. 

The eifects of alcohol vary greatly, however, in different individ- 
uals and in the same individual at different times. One person is 
rendered sentimental, another bellicose, while in a third there may be 
no appearance of excitement, the first distinct symptom being pro- 
found slumber. When drinking is indulged in in company, the excite- 
ment stage is a very common phenomenon, but if alcohol is taken 
without the exhilarating accompaniments of bright lights and exciting 
companionship, it is much less frequently seen, and the question has 
therefore arisen how far the environment produces the excitement in 
alcoholic intoxication. 

It may be stated at once that there exist two distinct views as to the 
action of alcohol on the central nervous system : the one stoutly upheld 
by Binz and his pupils, that alcohol first stimulates and then depresses 
the nerve cells ; the other championed by Schmiedeberg, Bunge and 
their followers, that it depresses the central nervous system from the 
beginning. The symptoms of excitement require no explanation on 
the first theory, which is rather to be looked on as the natural expres- 
sion of the facts observed. On the other hand, Schmiedebero: ex- 
plains them as not due to true stimulation of the motor areas, but 
as the result of these areas being freed from control by the weakening 
of the highest functions of the brain — the will and self-restraint. 
Even the smallest quantities of alcohol tend to lessen the activity of 
the brain, the drug appearing to act most strongly, and therefore in the 
smallest quantities, on the most recently acquired faculties, to anni- 
hilate those qualities that have been built up through education ami 
experience, the power of self-control and the sense of responsibility. 
The question is a most difficult one to decide, for on the one hand it 



134 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

has been shown that the simplest movement is the result of a combi- 
nation of motor and inhibitory impulses from the brain, while on the 
other hand the measurement of the relative strength of these impulses 
is one of the most difficult problems of biology. The advocates of the 
stimulant action point to the confidence in their own powers exhibited 
by intoxicated persons, to the brilliancy of the after-dinner speech, and 
to the excitement stage as evidences of the increased activity of the 
brain. But their opponents question whether the confidence is accom- 
panied by any really increased physical strength, and point out that 
the brilliancy of speech may be due to the environment and to the 
speaker having lost his habitual shyness and nervousness, and that the 
excitement is generally absent when the associations are different, or 
degenerates into a form which more distinctly resembles depression. 

More definite evidence for or against the stimulant action of alcohol 
has therefore been sought by comparing the amount of work which 
can be done with and without it ; and an apparent confirmation of 
Bunge's view has been found in the results of the use of alcohol by 
troops on the march, for repeated experience has shown that those regi- 
ments which were not supplied with alcohol marched farther and were 
in better condition at the end of the day than others to which it had 
been given. Forms of work requiring larger drafts upon the intel- 
ligence than the marching of soldiers are also performed less correctly 
with alcohol than without it ; thus typesetters can do more work and 
make fewer errors when they abstain from its use. The capacity for 
work depends not so much upon the actual strength of the muscles as 
upon the condition of the brain, and these experiments are therefore 
generally quoted as evidence of the depressant action of alcohol. 
Their results are not incompatible with the view that alcohol primarily 
stimulates the nerve cells, however, for Binz and his followers allow 
that the stimulation is transient and is followed by depression, and if 
a sufficient time elapse after the alcohol is taken, the stage of depres- 
sion is elicited and the total work may thus be reduced. A more exact 
method of examining the initial effects of alcohol on work is afforded 
by measuring at different intervals after the drug is given the work of 
which a muscle is capable before it is completely fatigued. This has 
been done in a number of experiments with the ergograph and the 
dynamometer, which have not all given the same result ; the majority 
of the investigators hold, it is true, that the initial effect is to increase 
the capacity for work (Scheffer), but the number of experiments is 
comparatively small and the liability to error very great; besides, 
several authors are inclined to regard the increase as due not to the 
central action of the alcohol, but to its acting as a muscle food or af- 
fecting the peripheral nerves. 

The measurement of intellectual work is, of course, much more 
difficult, and the results are very liable to misinterpretration, but 
Kraepelin found in a series of careful measurements of the simpler 
cerebral processes that the receptive and intellectual powers were weak- 
ened by very small quantities of alcohol, while the motor functions 



ALCOHOL. 135 

seemed to be facilitated by small, and retarded by large quantities. 
For example, a person under even a small dose of alcohol makes more 
errors than usual in adding a row of figures and in reading a series of 
unconnected syllables and apparently recognizes letters and words 
somewhat more slowly. It is interesting to find that the subject of the 
experiment is quite unaware of the inferiority of his work and is often 
persuaded that it is unusually good. Kraepelin's latest investigation- 
tend to show that this effect of alcohol lasts much longer than is gen- 
erally recognized, the mental equilibrium being reinstated only 12-24 
hours after even very moderate indulgence in alcohol. He leans to 
the view that alcohol weakens and paralyzes some parts of the brain, 
while primarily stimulating others, but brings forward no new evidence 
that this stimulation is not fictitious and really due to the removal of 
the barriers of self-restraint by the paralysis of higher areas. Jacobj 
found that small differences in weight could be estimated more correctly 
under alcohol than in the normal condition of the brain, and this would 
seem at first sight to indicate primary stimulation, but he believes that 
the true explanation is a retardation of the cerebral processes. The 
sensation of pain is also found to be lessened by even small quantities 
of alcohol. Xo unequivocal evidence of the initial stimulant action on 
the brain has yet been adduced, for each new feature may be inter- 
preted as really due to the depression of controlling or inhibitory func- 
tions. Of course, there is no absolutely convincing proof that no 
stimulation of the motor areas occurs, and no physiological proof of 
the existence even of controlling areas can be adduced, much less of 
their paralysis by alcohol. On the other hand, no other known drug 
stimulates the motor areas only, without increasing the activity of the 
lower parts of the system at some stage of its action, and the advocates of 
the stimulant action have to consider chloroform and ether also brain 
stimulants, for they cause a stage of excitement very similar to that pro- 
duced by alcohol, and, in fact, have been used as habitual intoxicants. 

Baratynsky has recently made an attempt to demonstrate experimentally 
the correctness of Schmiede berg's view, that the excitement of poisoning 
with the fatty series is really due to depression of the controlling functions, 
and although the drugs he used were chloroform, urethane, chloralamide 
and sulphonal, his experiments may be mentioned here. He finds that frogs 
are first excited and then depressed by these poisons, but that if the parts of 
the brain anterior to the optic lobes be destroyed no excitement is evinced. 
Uninjured pigeons also develop excitement under alcohol and other fatty 
narcotics, but if the cerebrum be removed before the drug is administered 
no excitement is observed. But these results indicate merely that the ex- 
citement is cerebral in origin, without determining whether it is caused by 
the removal of inhibition or by true stimulation. 

Acute alcoholic intoxication leads to very distinct alterations in the histo- 
logical appearance of the cells of the central nervous system, which have 
been described by Dehio, Stewart and others. The chief change noted by 
them consists in replacement of the chromatin network by line granules, 
which in turn seem to become dissolved in the general cytoplasm. Staining 
reagents, therefore, give rise to a diffused coloration of the cell rather than 
to localized masses of color, such as are seen in the normal cell. The den- 
drites are shortened and exhibit rounded nodosites along their course. 



136 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

In the lower parts of the central nervous system the evidences of 
primary depression are less open to question. For example, the coor- 
dination of the movements suffers at an early stage in alcohol drink- 
ing, long before the generally recognized forms of lack of coordination, 
such as indistinct speech and staggering, appear. In the spinal cord 
alcohol causes a depression of the reflex irritability, which passes into 
complete paralysis some time before the respiration ceases. 

The medulla oblongata is the last part of the central nervous system 
to be acted on by alcohol, or at any rate to undergo complete pa- 
ralysis. The Respiratory and Circulatory Centres preserve their func- 
tions long after the occurrence of complete unconsciousness and the 
disappearance of the ordinary reflexes. The same question has been 
raised in regard to the respiratory centre, as has been already dis- 
cussed in the consideration of the brain, and the same two opposing 
views have been upheld. These are of greater importance as regards 
the respiratory centre, because the advocates of the stimulation theory 
advise the use of alcohol in conditions of the respiration in which 
it is directly contraindicated if the other view be the correct one. 
The question here is apparently much more simple, because the ac- 
tivity of the respiratory centre can be estimated directly by measuring 
the number of the respirations and the amount of air inhaled during 
each ; but a large number of such experiments have been performed 
with very varying results. If the number of the respirations be 
counted in a person in the excitement stage of alcoholic intoxication, 
it is often found to be much greater than normally, but this may be 
due to the muscular movements and need not indicate any direct action 
of the drug on the medullary centre. And, of course, this excitement 
stage is not elicited in therapeutics, and the value of alcohol as a res- 
piratory stimulant must therefore be estimated in cases in which no 
such excitement is caused. A number of such estimations have been 
made in man and animals, and on the whole the evidence shows that 
in man even when no excitement is produced and in some instances 
even when sleep follows, the amount of air inhaled is larger than before 
the drug was administered (Jaksch, Zuntz and Berdez, Geppert, 
Weissenfeld, Wendelstadt). This may not indicate a direct stimula- 
tion of the respiratory centre, however, for the increase is often not 
greater than that following an ordinary meal and may therefore be 
attributed to the respiratory centre being indirectly affected by the 
activity of the stomach and intestine. And it is to be noted that 
alcohol may have more indirect effect on the respiration than ordi- 
nary food because it is so much more irritant to the stomach wall. 
These experiments failing to determine whether the respiratory centre 
is directly stimulated in man, another method has been employed by 
Loewy in which the excitability of the centre was estimated by its 
response to the stimulus of an increase of the carbonic acid in the 
blood. Unfortunately his experiments were too few to permit of 
general inferences, but they lend no support to the theory that the 
irritability of the centre is increased. There is therefore no sufficient 




ALCOHOL. 137 

evidence that the respiratory centre is directly stimulated in man and 
the increase in the amount of air inhaled may be due to the peripheral 
action of alcohol. 

In the dog, no acceleration of the respiration occurs after alcohol, while 
in the rabbit, on the other hand, the respiration is much accelerated, and 
the amount of air inhaled shows a corresponding increase. Jacquet lias 
attempted to show that this is due to the local action of the alcohol, and not 
to any direct effect on the nervous sytem, but his results have been disputed 
by Wilmanns ; Singer also refuses to recognize the changes in the rabbit's 
respiration as an indication of direct action on the respiratory centre and is 
disposed to attribute them to the irritation of the stomach and the increased 
muscular activity which is rendered necessary by the loss of heat entailed 
by the dilatation of the cutaneous blood vessels. Besides, the respiratory 
mechanism of the rabbit seems to differ considerably from that of man and 
of the other mammals, for in the last stages of chloroform and ether poison- 
ing a very remarkable acceleration of the respiration occurs, w r hich would 
seem to be similar to the acceleration under alcohol, but can scarcely be 
supposed to be due to stimulation of the centre. This fact seems to invali- 
date any inferences as to the behavior of the human respiration drawn from 
that of the rabbit under these drugs. 

In short, there is no unequivocal evidence that the increase in the respi- 
ration under alcohol in health is due to direct stimulation of the respiratory 
centre, while on the other hand, no depression of the activity of this centre 
occurs except at a late stage of alcohol poisoning. Alcohol is often said to 
slow the respiration in fever patients and to stimulate it in cases of shock. 
In the first case, however, there need be no direct action on the respiratory 
centre, for it seems much more likely that the improvement (when present 
at all) is due to the alcohol lessening the excitement through its narcotic 
action. The pathology of shock is so little understood that it would be use- 
less to attempt to explain its therapeutics, but if, as is held by many, shock 
is a condition of great inhibitory activity, the action of alcohol may be 
explained by its depressant effects, while on the other hand, it is difficult to 
explain these two contradictory effects on the theory that alcohol is a 
stimulant. 

The whole question might be supposed to possess merely theoretical 
interest ; in cases in which the respiration is insufficient it would seem 
that it is of little moment whether it is improved by a direct increase 
in the activity of the centre, or by some peripheral action. This is 
not correct, however, for if the respiration is increased only to cope 
with the products of the augmented activity of the alimentary tract, 
the general economy may profit little. On the other hand, if the air 
inspired is augmented in a greater ratio than these products, as is the 
case when the centre is directly stimulated, the advantage to the organ- 
ism is correspondingly great. 

The action of alcohol on the Circulation is no less disputed than that 
on the respiration, and the same divergence exists in the statements of 
the supporters of the stimulation theory. The real foundation for this 
view is here again the acceleration of the pulse during the excitement 
of alcoholic intoxication, which may be due to the increased muscular 
effort and not to any direct action on the heart. Jacquet lias shown 
that the pulse rate is unaltered by alcohol in normal cases, provided 
that no excitement be produced by the environment. In animals 



138 ORGANIC DRUGS ACTING AFTER ABSORPTION 

Fig. 2. 










Tracing of the dog's ventricle under alcohol. 8 c.c. (2 drs. ) of 50 per cent, alcohol were injected into 
a vein during this tracing, but no effect whatever is visible in the movement of the heart. During 
systole the lever moves upwards during diastole downwards. (The tracing is to be followed from 
left to right. ) 

Fig. 3. 




Tracing of the movements of the ventricle (lower) and auricle (upper) of the dog when a large dose 
(20 c.c. or % oz. ) of 50 pt-r ceut. alcohol is suddenly thrown into a vein. The levers move upwards 
during systole, downwards during diastole. A, normal. B, injection. The systole of the auricle is 
very much weakened, the diastole is less affected. The ventricular systole is comparatively little 
changed, although it also is a little weaker. The effect passes off very rapidly, so that at the eud of 
the tracing both chambers have almost recovered. A very similar effect is seen under chloroform. 
(Fig. 9.) (The tracing is to be followed from right to left.) 



ALCOHOL. 139 

alcohol has no effect on the pulse rate, unless given in very large quan- 
tities, when it produces effects similar to those described under chloro- 
form and ether — weakening of the auricular systole, and later of the 
ventricular, with distention of both cavities and slowing. The effects 
of alcohol on the heart are, however, very much less marked than 
those of chloroform, for Dieballa found that 48 times as much alcohol 
as chloroform was required to modify the movements of the frog's 
heart, and that in order to bring it to a standstill 192 times as much 
alcohol was required. 1 Alcohol having been shown not to increase the 
rate of the heart, its advocates have begun to state that the force of 
the contraction is augmented, without however bringing forward any 
evidence of this worthy of attention. In animal experiments, it has 
been shown that the first effect of alcohol on the heart is lessened 
efficiency and weakness of the contractions. (Figs. 2 and 3.) 

The flushing of the skin which occurs in alcoholic intoxication would 
seem to point to some vascular action, but it is impossible to say at 
present what the nature of this action is. It indicates dilation of the 
skin vessels, but whether this is of central or peripheral origin, whether 
due to stimulation of dilator centres or paresis of vaso-constrictors, is 
unknown. The widening of the blood path through this dilation is 
but slight, and produces little or no fall in the general blood-pressure. 
Very large quantities of alcohol cause a marked fall in the arterial 
tension, through weakening the vaso-constrictor centres and the heart 
muscle, but the quantities of alcohol required to cause any great fall 
in blood-pressure are far in excess of those used in therapeutics. It 
has been suggested that the widening of the arteries may in itself 
relieve the heart by lessening the resistance against which it has to con- 
tract, but it has yet to be proved that any marked dilation of the vessels 
occurs before the direct action on the heart muscle. Some evidence of 
this is forthcoming, it is true, for Hammeter found the velocity of the 
blood current increased by alcohol, but he does not state the quantity 
used in his experiments. 

The slowing of the heart which often follows the administration of 
alcohol in fever, would seem due rather to its diminishing the cerebral 
excitement than to its direct action on the heart. On the other hand, 
the alleged improvement of the circulation in shock may be due to a 
reflex from the irritant local action, and certainly would not seem to 
require any direct cardiac action for its explanation. 

Alcohol has no effect on Muscle or on peripheral Nerves when it is car- 
ried to them by the blood, but when it is applied directly to muscle, it 
weakens its contractions. When a frog's nerve is exposed to alcoholic vapor 
its irritability is first increased and later diminished if the quantity applied 
be large enough. This fact has been used by Sehefler to explain the results 
of ergographic experiments in which the amount of work done under alcohol 
is at first augmented. He regards this augmentation as due not to central 

1 An exception to the general rule is found in the embryo heart of the chick, which 
according to Pickering, is much accelerated by the direct application of alcohol, but 
this may be due to the local irritant action rather than to the general effects. 



140 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

stimulation, but to the peripheral processes being facilitated. The sensory 
fibres are said to be depressed before the motor. 

The effect of alcohol on the Digestion has been the subject of many in- 
vestigations, both from the clinical and the experimental point of view. 
There exists a widespread belief in both lay and medical circles that 
small quantities of alcohol taken before a meal increase the appetite, 
while after food they accelerate the digestion. It is obvious that 
alcohol may affect digestion either by altering the activity of the fer- 
ments in the digestive canal, or by altering the secretion, movement, 
or absorption of the stomach and intestine. The digestive power of 
the ferments outside the body has been found to be unaltered or 
slightly increased when alcohol is present in very small quantity. In 
a solution of 5-10 per cent, of alcohol or of spirits, however, the gas- 
tric juice digests very much more slowly than normally, and the pan- 
creatic secretion is affected prejudicially by even smaller quantities. 
(Chittenden and Mendel.) Very large quantities of alcohol precipitate 
the proteids, but it is unlikely that sufficient alcohol to produce this 
effect ever remains in the stomach for any length of time. The malt 
liquors and wines are much more detrimental to the digestive ferments 
than pure alcohol or spirits, and the augmentation of the activity of the 
ferments is so slight in any case that it does not seem likely that it 
plays any important role in the effects of alcohol on the stomach. 

The presence of alcohol in the mouth causes (according to Chitten- 
den, Mendel and Jackson) a very appreciable increase in the secretion 
of the saliva, presumably by reflex action. As regards the action on 
the stomach wall, it is to be remembered that alcohol, even in compar- 
atively dilute solution, is an irritant, and therefore leads to increased 
activity of the cells, a more active circulation in the organ, and prob- 
ably to a more rapid secretion of both acid and solids of the gastric 
juice. But apart from this local action on the stomach, it appears to 
exert a specific action on the secretion after its absorption into the cir- 
culation. For when it is injected into the dog's rectum, a profuse 
secretion from the gastric mucous membrane follows, and when part of 
the stomach is isolated from the rest of the organ, so that alcohol given 
by the mouth fails to enter it, this part still shares in the secretion. 
According to Radzikowski, the pepsin secretion is not always cor- 
respondingly augmented, the alcohol not accelerating the formation of 
pepsin from propepsin but merely leading to the secretion of the pepsin 
preformed in the cells. Similar effects have been obtained in man by 
Spiro, who administered alcohol by the rectum. It has been further 
demonstrated that the absorption of fluids from the stomach and bowel 
is much accelerated by the addition of alcohol (Brandl, Scanzoni, Farn- 
steiner, Tappeiner), and the movements of the stomach are also aug- 
mented by moderate quantities. (Klemperer, Batelli.) 

Digestion in the stomach may thus be influenced in two opposite di- 
rections when alcohol is administered in the usual form of wine, spirits, 
or beer. The action on the ferments is deleterious while the changes 
in the stomach wall, the increased secretion and movement and the 






ALCOHOL. 141 

accelerated absorption, are beneficial in many cases. These two opposing 
factors may neutralize each other, as in the dog in which the rate of diges- 
tion is scarcely altered, the retarding effects of alcohol on the proteolysis 
being compensated for by the more abundant secretion of the June, 
which continues after the alcohol is absorbed, and therefore after its 
deleterious effects on the fermentation have disappeared. (Chittenden, 
Mendel and Jackson.) In man the result varies, the one factor pre- 
dominating in some cases, the other in others. Thus, while Kretschy 
and Buchner found that the digestion of proteids in the human stomach 
was distinctly retarded by alcohol and beer, Eichenberg, Wolffhardt 
and others state that small quantities of alcohol or wine accelerate the 
digestion, and Gluzinsky came to the conclusion that as long as alcohol 
remains in the stomach the digestion is retarded, but that after its ab- 
sorption the digestion progresses more rapidly than if no alcohol had 
been given. Zuntz and Magnus-Levy have shown that the addition of 
beer to the dietary does not affect the absorption and utilization of the 
food by the tissues. It is not unlikely that the taste has some influ- 
ence on the result, that in those who enjoy the taste of alcohol, it in- 
duces a more rapid secretion and an improved digestion, while in those 
to whom it is disagreeable, the secretion is less altered. 

The divergence of opinion exists only in regards to the effects of 
small quantities, for all are agreed as to the deleterious action of any 
but moderate doses of alcohol on the digestion. After large quantities 
the irritation of the stomach wall is so great that nausea and vomiting 
are induced. There is every reason to suppose that this is due to the 
local irritation, and not to the action of the absorbed alcohol on the 
nervous centres. A large dose of concentrated alcohol sometimes 
leaves evidence of its irritant action in redness and injection of the 
mucous membrane and, it is said, in ecchymoses, but in most cases 
of fatal poisoning no such appearances are to be observed after 
death. 

Is Alcohol a Food ? — This has long been discussed, and that with 
more passion and prejudice than are generally elicited by pharmacolog- 
ical questions. It was formerly supposed that the alcohol absorbed 
from the stomach was excreted unchanged by the lungs, skin and 
kidneys, and therefore gave up no energy to the body in its passage 
through it. But it has been shown that only the small amount of 
from 5-10 per cent. 1 of the ingested alcohol is really excreted in this 
way, and that mainly by the kidneys and lungs, the skin taking prac- 
tically no part in the excretion. The rest of the alcohol absorbed 
from the stomach and bowel, amounting to over 90 per cent., undergoes 
combustion. The fact that none of the products of the combustion 
have been isolated from the body does not invalidate this statement, 
for the corresponding products of sugar are not known, but there is no 

decent investigations suggest that even this is too high a valuation for the alcohol 
excreted and that only 2-3 per cent, of that ingested escapes oxidation. In particular 
there seems reason to question whether anything more than traces escape by the lungs. 
A very small quantity appears in combination with glycuronic acid in the urine of 
some animals, notablv the rabbit. 



142 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

doubt that sugar is oxidized in the body. 1 According to Grehant's 
recent work, the oxidation of alcohol progresses slowly, appreciable 
amounts being found in the blood twenty-four hours after its ingestion ; 
this accords with Kraepelin's statement that its effect on the brain can be 
detected for 12-24 hours. In undergoing combustion alcohol gives up 
energy to the body, and therefore is technically a food. This statement 
has met with a great deal of opposition, and the mere fact that alcohol 
gives up energy to the body does not constitute it an advisable food in 
all conditions. For example, the question might be raised whether 
alcohol does not require an amount of energy for its absorption equal 
to that liberated by its combustion, or whether its action on the nervous 
centres does not produce a greater waste of force than the food itself 
supplies. Both of these have been answered by experiments in which 
the carbonic acid excretion of the body has been measured before and 
after alcohol. Zuntz and Berdez and Geppert have shown by this 
method that after alcohol is taken, a slight rise of 5-10 per cent, occurs 
in the output of carbonic acid ; that is, a small amount of extra com- 
bustion goes on, a certain amount of energy is required for the absorp- 
tion, but this is not greater than that required for the absorption of 
any other form of food. And the total amount of carbonic acid ex- 
creted in 24 hours is not appreciably altered by alcohol, so that alcohol 
taken in addition to the ordinary food is either itself transformed into 
tissue, or undergoes oxidation instead of some substance which in turn 
is used to build up the body. Strassmann has shown that animals that 
receive alcohol tend to lay on more fat than others receiving the same 
food without alcohol, and this is in accord with the common observa- 
tion of the obesity of alcohol drinkers. Alcohol, therefore, acts as a 
substitute for fats and carbohydrates in the food to some extent. 

It has long been recognized that when insufficient fat and carbohy- 
drate is supplied to the body, the proteids are drawn upon to make 
good the deficiency and the nitrogen eliminated rises accordingly. On 
the other hand, when the fats and carbohydrates of the food are in- 
creased, the organism economizes its proteid and the nitrogen tends to 
fall. This is the most accurate method of testing the food value of 
non-nitrogenous substances, and alcohol has been the subject of a num- 
ber of such investigations. The divergent results have given rise in 
the last few years to a series of experiments which promise to become 
classical for the extraordinary patience and conscientiousness exhibited 
by those engaged in them as well as for the complete agreement in the 
results obtained by investigators who approached the subject with 
opinions which were diametrically opposed. These experiments, which 
may be cited as models of investigations in metabolism, were performed 

1 It has been suggested that the oxidation of alcohol in the body may not give rise 
to the same products as its oxidation in the chemical laboratory. If aldehyde were 
formed it would be excreted in part by the lungs and kidneys, for aldehyde injected 
into the blood at once appears in the breath and urine. Acetic acid has never been 
identified with certainty after alcohol, but formic acid is excreted after methyl alcohol, 
and it therefore seems probable that ethyl alcohol is oxidized to noetic acid immediately, 
and that this at once undergoes further decomposition. 



ALCOHOL. 



143 



bv Xenmann, Atwater and Benedict, and Rosemann and his pupils. 
The results may best be illustrated by an account of Neumann's 
first experiment. 

This lasted 35 days divided into six periods. The proteids of the 
food and the carbohydrates remained constant throughout while alcohol 
was substituted for part of the fat for some time (see Fig. 4). Dur- 

Fig. 4. 




The effect of alcohol on nitrogen elimination. The wave-line represents the nitrogen excreted. It 
rises rapidly in the second period when the fat of the food was reduced to one half, but soon falls in 
the third period where alcohol was substituted. 100 g. of alcohol is chemically equivalent to 78 g. 
of fat. ( After Neumann. ) 



ing the first five days, the nitrogen excreted was practically equal to 
that of the food (nitrogenous equilibrium), while during the next four 
days one half of the fat of the food w r as omitted and the immediate result 
was an increase in the nitrogen excreted, indicating that the proteids of 
the body w T ere being drawn upon to make good the deficit in the fat of 
the food. The next ten days a quantity of alcohol chemically equivalent 
to the fat deficit was taken and the nitrogen elimination slowly fell to 
the normal (equilibrium). In the first five days of this period, however, 
the nitrogen remained high, showing that alcohol did not at first replace 
the fats completely. In the fourth period of six days, the same 
amount of fat was given as at first, while the alcohol was continued, 
and the nitrogen fell much below the amount ingested ; i. e., the alcohol 
again led to a saving of the proteids. Next, both alcohol and fat 
were omitted for four days and the proteid tissues were again drawn 
upon. Finally the original diet was resumed and the nitrogenous 
equilibrium was at once restored. From this experiment Neumann 
drew the conclusion that alcohol can replace a chemically equivalent 
amount of fat in the dietary, for otherwise the nitrogen would not 
have returned to the normal toward the end of the third period ; and 
alcohol given along with a sufficient dietary leads to a further economy of 
the proteids just as additional fat would ; otherwise the nitrogen would 
not have fallen below the point of equilibrium in the fourth period. 
Certain objections which were made to this experiment by Rosemann 



144 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

have been refuted by his own work and by Neumann's, so that both 
investigators are now in accord. 

The final result of all these investigations is that alcohol can take 
the place of some of the fat in the food, and leads to the same economy 
of proteid as the ordinary non-nitrogenous constituents of the dietary. 
The first three or four days during which alcohol is substituted for fat 
it has little or no tendency to economize the proteids, but this is true 
of other forms of food also, any sudden change in the non-nitrogenous 
food leading to a temporary increase in the nitrogen excreted, which 
persists until the tissues have become accustomed to the new dietary. 

Metabolism. — It was formerly supposed that alcohol economized the 
body tissues in some ill-defined way, by means of a direct action on 
the protoplasm of the cells ; as it was expressed, alcohol lessened the 
combustion of the tissues. There is no reason to suppose that alcohol 
in ordinary quantities has any action on the tissues save as a food, for, 
as has been mentioned, the oxidation of the tissues as measured by the 
oxygen absorbed and the carbonic acid exhaled is only affected as it is 
by any other food. When very large quantities of alcohol are taken, 
and depression and sleep follow, the combustion of the body is reduced, 
not through any action on the protoplasm generally, but through the 
muscular movements being lessened. In the same way, during the ex- 
citement stage, the carbonic acid exhaled is doubtless much increased, 
because more energy and more of the body tissues is used up in the 
violent movements. Of course, the oxidation of alcohol by the tissues 
saves fat from combustion, and it is possible that some bodies which 
would normally be oxidized in the organism may pass through it un- 
changed in the same way. Thus it is stated that less benzol is oxi- 
dized in animals under the influence of alcohol than in unpoisoned 
ones, and this is to be explained by the energy, which would ordi- 
narily be employed in oxidizing the benzol, being diverted to the 
combustion of the alcohol. The uric acid excretion does not seem 
to be changed in amount by alcohol even when given in large quan- 
tities. Paton and Eason found that the proportion borne by the 
urea to the total nitrogen of the urine is lower when alcohol is ad- 
ministered and infer from this that the function of the liver is 
disturbed. 

The Temperature of the body falls somewhat after the administration 
of alcohol, but this is not due to any diminution in the oxidation and 
in the heat formed, but to the greater output of heat from the dilation 
of the skin vessels. The fall in temperature is comparatively slight, 
seldom being more than J-l° C, but it would seem that exposure to 
cold causes a greater fallin the temperature after alcohol than in nor- 
mal conditions ; this is perhaps due to the temperature-regulating 
mechanism being rendered less sensitive by alcohol. 

The fall in temperature produced by alcohol is generally accompa- 
nied by a feeling of heat, and a thermometer applied to the skin may 
actually show r a rise of several degrees, because more warm blood flows 
through the dilated vessels. If much excitement and movement follow 



ALCOHOL. 145 

the ingestion of alcohol, no fall in the temperature may result, the in- 
creased heat formed during the movement compensating for the increased 
output, and in some cases a rise of temperature occurs from the same 
cause. Very large quantities of alcohol may lead to a fall in temper- 
ature of 3-5° C, owing to the lessened movements during uncon- 
sciousness. 

The alcohol which escapes combustion in the tissues is excreted by 
the kidneys and perhaps by the lungs. Traces are sometimes found 
in the sweat and milk, but there is no foundation for the legend that 
children may be intoxicated, or acquire a taste for strong drink from 
the alcohol absorbed in the milk of a drunken mother or svet -nurse. 
The amount and quality of the milk are unaffected by the adminis- 
tration of alcohol (Roseniann). 

Although alcohol seems to increase the urine to some extent, it can- 
not be said to be a powerful diuretic in itself, and it is quite unknown 
whether it acts on the kidney directly or not. Some of the spirituous 
liquors such as gin, produce a profuse secretion of urine, but this is 
due to their other constituents, and not to the alcohol. 

Alcohol is generally credited with aphrodisiac powers, that is, with 
increasing sexual desire, although no less an authority than Shake- 
speare states that it prevents the consummation of sexual intercourse. 
The unquestionable tendency toward sexual excess observed in intoxi- 
cation is due, not to any effects on the generative organs, but to the 
loss of self-control from the cerebral action of the poison. 

Alcohol has comparatively little bactericidal action at the tempera- 
ture of the body ; 50-70 per cent, alcohol is said to be more destruc- 
tive to germs than either stronger or weaker solutions. Xot only is 
it of little practical value in itself as an antiseptic, but many bodies 
which are antiseptic when dissolved in water, have comparatively little 
effect when dissolved in alcohol. (Compare p. 48.) 

It has long been recognized clinically that persons addicted to the use 
of alcohol show less resistance in acute disease and in operations accom- 
panied by shock than more temperate individuals, and in very intem- 
perate cases, the prognosis must be guarded in an attack which would 
ordinarily be accompanied with little danger. This has been confirnuMl 
by a number of experiments on animals which were subjected to treat- 
ment with alcohol and then inoculated with pathogenic germs 
(Laitinen). The results have invariably shown a greater susceptibility 
to infection and a greater mortality than in control animals which had 
received no alcohol. A similar effect was observed when toxines were 
injected instead of bacteria, and great difficulty was encountered in 
rendering animals immune to the diphtheria toxin if they had pre- 
viously been treated with alcohol. This has been attributed t«» 
pathological conditions induced in various organs and in evidence o( 
this it is stated that the alkalinity of the blood is reduced in these 
cases. 

Repeated doses of alcohol produce tolerance, which, although not 
so great as that acquired for morphine and nicotine, involves the pre- 
10 



146 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

scription of double or triple doses, in persons addicted to drinking. 
The close relationship between the narcotics of the fatty series is 
indicated by the fact that much more chloroform or ether than usual 
is required to anaesthetize persons in whom a tolerance for alcohol has 
been established. 

The other alcohols are mainly of interest as impurities of the preparations 
of ethyl alcohol. They all resemble it in their general effects, but differ 
from it in toxicity ; thus the poisonous dose becomes smaller with each CH 2 
added, propyl alcohol is more powerful than ethyl, butyl than propyl, and 
amyl than any of them. Ethyl alcohol, on the other hand, is more poison- 
ous than methyl, but the latter has a much more prolonged action, appa- 
rently owing to its slower oxidation in the body. Amyl alcohol, or fusel 
oil, is present in small quantity in most forms of spirits, especially when 
these are freshly distilled or "raw." It resembles ethylic alcohol in gen- 
eral, but is more irritant locally, and is believed by some authorities to have 
more deleterious effects in chronic poisoning than pure ethylic alcohol. 
This is not based on any very satisfactory evidence, however, and almost 
all the characteristic symptoms of chronic alcoholism have been produced 
in animals by pure ethyl alcohol. 

Preparations. 

Alcohol (U. S. P.) contains 91% of alcohol (C 2 H.HO) by weight. 

Alcohol Absolutum (U. S. P., B. P.), absolute alcohol, contains not more 
than 1 % , by weight, of water. 

Alcohol Deodoratum (U. S. P.) contains 92.5%, by weight, of alcohol. 

Alcohol Dilutum (U. S. P.) contains about 41%, by weight, of alcohol. 

Spiritus Rectificatus (B. P.), rectified spirit, contains 90 parts of pure alco- 
hol, by volume, and 10 parts of water (85.65%, by weight, of alcohol). 
There are four official dilutions in the B. P., containing 70, 60, 45 and 20 
per cent, of alcohol by volume respectively. 

Spiritus Frumenti (U. S. P. ), whiskey, contains 44-50 % of alcohol by 
weight, and is obtained by distillation of an extract of fermented grain. 

Spiritus Vini Gallici (U. S. P., B. P.), brandy, contains 39-47% of alco- 
hol by weight, and is obtained by the distillation of fermented grape juice. 

Mistura Spiritus Vini Gallici (B. P.), a mixture of brandy, cinnamon water, 
sugar and yolk of egg (about 17 per cent, alcohol). Dose, 1-2 fl. oz. 

Non-pharmacopceial spirits, which are used occasionally in medicine, are 
gin and rum. 

These Spirits all contain, roughly speaking, about one half as much alco- 
hol as the three concentrated alcohols of the U. S. P. or the rectified spirits 
of the B. P. They contain, in addition to the ethyl alcohol proper, numbers 
of other volatile substances, some of which are alcohols of the same series 
as ordinary alcohols (butylic, amylic, etc.), while others are of entirely 
unknown constitution — the cenanthic ethers. Brandy and whiskey act very 
much in the same way as pure alcohol, but are more powerful than would 
be expected from the percentage of alcohol alone. When freshly distilled 
they are much more irritant than when kept for some years. Numerous 
other preparations containing large quantities of alcohol, such as the spirits 
of the volatile oils, might also be included in this group, but they are not 
used, 'as a general rule, for the same purposes as the alcoholic preparations 
proper, and their effects are in part due to the volatile oils contained. 
Some of them have, however, been employed as intoxicants instead of 
brandy or whiskey, and Eau de Cologne and other essences have gained a 
certain notoriety as a means of secret drinking among women. The liqueurs 
are too numerous to mention, and their composition is extremely diverse. 
Many of them contain considerable quantities of sugar, and the combination 



ALCOHOL. 147 

of alcohol and sugar would seem peculiarly deleterious to the gastric mucous 
membrane. Others, such as cherry water (Kirschwasser), contain hydrocy- 
anic acid, and the others various bodies of the volatile oil series. None of 
them seem to have any properties which would recommend their use in 
therapeutics. 

The Wines and Beers are much weaker preparations of alcohol. The 
U. S. P. recognizes two forms of wine, Vinum Album (white wine) and 
Vinum: Rubrum (red wine, claret). These both contain 10-14^ of alcohol 
by weight, along with 1.5-3 fo of solid matter in the white wine and 1.6- 
3.5 fo in the red. The Vinum Xericum (sherry) of the B. P. contains not 
less than l§f of alcohol by volume, while the Vinum Aurantii (B. P.), or 
orange wine, contains 10-12 fo by volume. In addition, the wines contain 
the same volatile constituents as brandy, although in smaller amounts. 
Other wines are prescribed in medicine, some of which, such as port 
(15-20%), contain larger, and others smaller quantities of alcohol (hock and 
champagne 8-13%). The red wines contain a form of tannic acid derived 
from the skin of the grapes, and both red and white often contain consider- 
able quantities of acids, chiefly tartaric acid. The amount of sugar varies 
with the different wines, and in fact in wine from the same locality but of 
different seasons. These constituents may lend to the wines a local dele- 
terious action on the stomach, more especially when they are taken habitu- 
ally. Champagne and the other sparkling wines contain large quantities of 
carbonic acid, which acts as a stimulant to the gastric mucous membranes. 
Champagne is considered one of the most "stimulant" of alcoholic prepa- 
rations, although it contains a very low percentage of alcohol compared with 
spirits, a fact which is of some significance in the explanation of the ' ' stim- 
ulant " effects of alcohol. 

The beers are not pharmacopceial, and are less frequently advised than 
the other preparations. They generally contain a comparatively small per- 
centage of alcohol (4-10%), along with a large amount of solids. These 
solids consist mainly of dextrin, sugar and other starch products, which retard 
the absorption of the fluid, but are of considerable value as foods. The hops 
added in the preparation have probably no action save as bitter stomachics. 
The alcohol of beer is comparatively slowly absorbed owing to the colloid 
constituents, and this allows time for fermentation changes in the sugars and 
dextrins, which may perhaps account for the discomfort produced by malt 
liquors in persons of feeble digestion. When beers and porter do not de- 
range the digestion, they are the most nutritive of all the alcoholic prep- 
arations, owing to the large amount of carbohydrates they contain. 

Therapeutic Uses. — Alcohol is used externally in very dilute solution 
as a cooling application to the skin, and in threatening bedsores, in 
which it is often applied as brandy, whiskey, or dilute alcohol in order 
to harden the epidermis. It has been employed as an antiseptic and 
mild irritant to broken surfaces, and if applied to the skin in concen- 
trated form, and especially if kept from evaporation, acts as a rubefa- 
cient and irritant. In the form of diluted claret it is not infrequently 
used as an astringent gargle. 

The indications for the internal use of alcohol are ill defined, and 
cases which one physician would treat with alcohol, often seem to pro- 
gress as favorably without it in the hands of another. It is not suffi- 
ciently recognized that this drug possesses several different qualities, as 
local irritant, narcotic and food and tiiat while one property considered 
alone might render it unadvisable in a given condition, the deleterious 
effect induced in this direction may be more than counterbalanced by 



148 ORGANIC DRUGS ACTING AFTER ABSORPTION 

its valuable results in other directions. At the same time it would be 
preferable in most cases to substitute for this conjunction of good and bad 
properties, other drugs with a less extended sphere of action. One 
series of symptoms which is often treated with wines is of gastric 
origin, and is manifested in want of appetite and enfeeblement of the 
digestion ; in some of these cases the alcoholic preparations seem to be 
beneficial, while in others they appear to be positively harmful. This 
may be explained by the effect of alcohol on secretion and absorption, 
only those cases in which secretion is deficient being benefited, but the 
tastes of the patient are also an important factor ; if he enjoys the taste 
and odor of wine, its administration may promote his appetite, while, 
on the other hand, if he has a distaste for wine, it will prove harmful. 
There is no question that the functions of the stomach are increased by 
pleasing, and retarded by unpleasant tastes and odors. In these cases 
"dry" wines are to be preferred, as the sugar of the sweet wines may 
irritate the stomach ; champagne may be used, and the wine ought to 
be given immediately before or during a meal. 

Cases of hemorrhage, shock, and other forms of severe and sudden 
depression of the heart and central nervous system are very frequently 
treated by the administration of strong alcoholic preparations, such as 
brandy and whiskey, this treatment being based upon the belief that 
alcohol is a cardiac and respiratory stimulant, the grounds for which 
have already been examined. It is extremely difficult to estimate the 
value of a remedy in these conditions, and it is possible that the irri- 
tant action of alcohol in the stomach may increase the activity of the 
medullary centres reflexly, or that by its narcotic action it may lessen 
the anxiety- and pain of the patient. On the other hand, in cases of 
inhibitory slowing of the heart it may aid by lessening the activity of 
the vagus centre in the medulla. But the beneficial effects of alcohol 
in these cases has been much questioned in recent years and the belief 
that it is of little value is certainly more widely held at present than 
at any previous time. 

In sudden chill with a tendency to fever, alcohol is often of great 
benefit, especially when taken in the form of brandy or whiskey 
diluted with hot water. Its efficacy here would seem due to the relief 
of the congestion of the internal organs by the return of the blood to 
the skin. 

In many cases of acute inflammatory disease, the prescription of alco- 
hol seems to be attended with benefit, while in others it seems to rather 
increase the severity of the symptoms. No special indications can be 
given for alcohol in these cases, and the physician must be guided 
by its effects. An old rule advised that if the pulse becomes slower, 
the temperature falls, the respiration is deeper, the nervous symptoms 
are ameliorated and the skin becomes moister after the administration 
of alcohol, the treatment ought to be continued ; but this is merely 
equivalent to advising the continued administration of alcohol when it 
is found to improve the symptoms. The effect of alcohol in these 
cases is often said to be a stimulant one on the heart and central nerv- 



ALCOHOL. 149 

ous system, but it would rather seem to allay the irritability of the 
nervous centres, and thus reduce the delirium and slow the heart and 
respiration by lessening the muscular movement. Moreover, the tis- 
sue waste is much increased in fever, and at the same time the food 
absorption is less than normally, so that many of the symptoms may 
be due to starvation of the tissues. Alcohol is more readily absorbed, 
and demands less energy from the digestive organs than fats and 
starchy foods, and at the same time has a higher value as a producer 
of energy than sugar. It cannot supply the place of the nitrogenous 
foods, but given along with them, may lead to a greater economy of 
the tissues. It is to be remarked that according to Neumann alcohol 
fails to have this effect, at any rate in normal individuals, until it has 
been given for several days, so that if it is to be used as a food, it 
ought to be given early in the disease. Strong wines or diluted spirits 
are generally employed here and ought to be given in small quantities 
frequently. Alcohol was formerly advocated especially in septic con- 
ditions, and here it may be of value on the same grounds as in acute 
fevers, although it does not seem to have any specific action in septic 
disease, as was once believed. A protest has recently been raised 
against the use of alcohol in these cases, on the ground that animals 
subjected to alcohol succumb more readily to infection than controls 
which have received no treatment, and this has been shown to be true 
even when the dose of alcohol was proportionate to that often advised 
in the treatment of these cases in man (Laitinen). This is undoubtedly 
an objection of great weight, but it must not be forgotten that though 
alcohol may be deleterious in this way, this may be more than com- 
pensated for by its value as a food, and by its narcotic effects allaying 
the nervous irritability and promoting sleep ; this narcotic action may 
very well be conceived to be of benefit to man, while actually preju- 
dicial to animals. 

In some chronic forms of nervous disease alcohol may also be of 
value, although its administration must always be guarded, owing to 
the tendency to the formation of the alcohol habit. Thus, in some 
forms of melancholia and of neuralgia it gives relief, partly probably 
through its depressant action on the brain and partly from its local 
action on the digestion. Some authorities recommend the use of alco- 
hol in small quantities in cases of distress of mind from any cause, 
such as grief, business anxiety or depression, and undoubtedly alcohol 
improves these conditions by its narcotic action on the brain. But 
the danger of the alcohol habit is so great, that many physicians refuse 
to take the responsibility of prescribing the drug in these cases. 

In chronic conditions of cachexia and loss of flesh in general, and 
during convalescence, alcoholic preparations are often advised simply 
as foods, and in these cases the ales, beers and porters are generally to 
be preferred to the others, provided always that the stomach is not 
irritated by them, as they contain other food-stuffs of value in addition 
to the alcohol. 

In poisonous snake bite, alcohol is generally administered in enor- 



150 ORGANIC DRUGS ACTING AFTER ABSORPTION 

mous quantities, either as whiskey or brandy, but it seems open to 
question whether it is really of value in these cases, and its action on 
the normal tissues certainly gives no indication for its use here. 

Alcohol is of value as a mild hypnotic, a comparatively small quan- 
tity taken before retiring being often sufficient to secure quiet and 
refreshing sleep. Beer or spirits and water is generally used for this 
purpose. 

Brandy has a certain reputation in the treatment of the milder 
forms of diarrhoea, while the other spirits have no effect in this condi- 
tion. The means by which this effect is accomplished are unknown. 

In the prescription of alcohol, the ordinary spirits, brandy or whis- 
key, are very much more frequently advised than the purer prepara- 
tions, as the latter are more apt to pall upon the taste of the patient. 
Both of these spirits ought to be diluted with at least an equal quan- 
tity of water. The wines are more used in chronic conditions, although 
diluted spirits may be advised here also. Beers are employed only in 
debility unaccompanied by gastric symptoms. 

Alcohol can be given to children in relatively larger quantities than 
to adults, and again in old age no such reduction in the dose is required 
as in the case of many other drugs. Where a tolerance for alcohol has 
been established, the dose has often to be more than doubled in order 
to have any effect, and in acute febrile conditions very large quantities 
of alcohol are often given without detriment, though it seems question- 
able whether an equally beneficial result could not be attained with 
much smaller doses. In gastric irritation, most preparations of alco- 
hol are contraindicated, but champagne is often of benefit in checking 
vomiting, especially that of pregnancy and of seasickness, this effect 
being due to the carbonic acid, not to the alcohol. In nephritis and 
other inflammatory conditions of the genito-urinary tract, alcohol is 
generally avoided on account of its supposed effects on the epithe- 
lium. 

In regard to the habitual use of alcohol by healthy persons all 
authorities agree that it is a luxury, that it is entirely unnecessary for 
the growth and maintenance of the body, but that taken in moderate 
quantities it is harmless, except from the danger that this may lead to 
the habit being formed. The habitual indulgence in alcohol to excess 
is more easily intelligible than some other chronic intoxications, for, 
unlike nicotine, alcohol is taken not only for its local effects on the 
organs of taste and on the mucous membranes of the mouth and 
stomach, but also for its action on the brain in numbing the con- 
sciousness of unhappiness, and this weakening of the higher sensibilities 
by drink is generally the object sought by the drunkard. He finds 
that under alcohol his habitual depression disappears, and he loses the 
sense of degradation and remorse which possesses him when sober. 
The depression returns in exaggerated form after the effects of the 
drug have passed off, but it can be removed again by the same means 
and in this w T ay the habit is formed, each successive dose being 
rendered necessary by the depression produced by its predecessor. 



ALCOHOL. 151 

This descent into chronic drunkenness is facilitated by the lessening 
of the self-control owing to the action of alcohol on the brain. The 
victim may form the best of resolutions, but his impaired will power 
and self-control are unable to carry them out. 

The symptoms of Chronic Alcoholism are unfortunately common, but 
may be treated better in detail in connection with various forms of dis- 
ease, with which they are associated more closely than with the effects 
produced by the medicinal use of the drug. The earliest symptoms 
are generally observed in the stomach, throat and larynx, and consist 
of a chronic catarrh, which is often accompanied by skin affections, 
such as injection of the cutaneous vessels (especially of those of the 
face), acne or pustular eruptions. The irritation spreads from the 
stomach to the liver and kidney, and produces fatty degeneration and 
necrosis of the cells, followed by increased growth of the interstitial 
connective tissue, and cirrhosis of these organs. The fatty degenera- 
tion is also found in the arterial walls throughout the body, and causes 
atheroma and arterio-sclerosis, which may lead to small aneurysmal 
dilatations, ecchymoses, or apoplexy. The heart undergoes more or 
less fatty change, which is accompanied by dilatation and weakness. 
In the central nervous system, the nutrition is imperfect owing to the 
vascular changes, but in addition to this, alcohol has a special action 
on the neurons, which is betrayed by the disappearance of the chro- 
matin granules, and eventually by shrinkage of the whole cell. The 
dendrites show moniliform enlargements along their course, and in the 
later stages the finer dendrites disappear entirely. These alterations 
in the central nervous system lead to impairment of memory, self- 
control and the other higher mental processes. Tremor, convulsive 
attacks, hallucinations and mania are eventually followed by idiocy 
and paralysis in the worst forms of the disease. The peripheral nerves 
seem to be acted on directly as well as through the changes in the 
centres, for neuritis has been frequently observed, ending in local 
paralysis. A form of amblyopia commencing by atrophy of the retinal 
ganglion cells and later extending to the fibres of the optic nerve has 
recently received some attention ; it seems to be more readily elicited 
by methyl than by ethyl alcohol. A characteristic result of chronic 
alcoholism is delirium tremens, an acute attack of insanity, which is 
liable to occur after any shock, such as hemorrhage or acute disease, 
but which is said to be also produced by the sudden withdrawal of 
alcohol, and sometimes occurs without any apparent immediate cause. 
It is characterized by tremor, perspiration, sleeplessness, fear, ex- 
citement and hallucinations of the various senses, which differ from 
many other hallucinations of insanity in consisting of the multiple 
appearance of the same object. These objects are often animals, 
such as snakes, rats, dogs, but the hallucinations are not confined to 
those of sight, for whispering voices are complained of not infre- 
quently. 

The more severe forms of chronic alcoholism arc confined almost 
entirely to the drinkers of undiluted spirits. Beers and wines seldom 



152 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

have any distinct action on the brain in themselves, unless spirits are 
also indulged in. The abuse of the weaker preparations of alcohol is 
always liable to lead to that of the stronger, however, as tolerance is 
established and the former lose their effect. The combination of spirits 
and malt liquors is said to be more liable to produce delirium tremens 
than the abuse of either alone. 

The disastrous effects of the abuse of alcohol are seen in the statistics 
of the hospitals, prisons, and asylums, and unfortunately these show 
an increase in the number of victims almost every year and in nearly 
all countries, but more especially in those in which the population is 
addicted to spirits. In Prussia, in 1886-1888, 11 per cent, of the 
cases admitted to the insane asylums were diagnosed as directly due to 
alcoholic excess, while in one of the Berlin asylums the enormous per- 
centage of 47.4 of the admissions were found to be addicted to alcohol. 
In France, in 1888, one eighth of the cases of suicide were due to 
alcoholic excess. In Paris, 72 per cent, of the convicted criminals in 
one year were found to be chronic alcoholists, while the proportion in 
Berne Canton was about 40 per cent. These numbers are officially 
certified to be correct, but give only an imperfect idea of the deplor- 
able results of alcoholic abuse, as only the more extreme cases come 
under the categories of criminals or lunatics, and the enormous num- 
ber of cases of disease directly caused or aggravated by the lesions 
due to alcohol escapes recognition. At the same time, it is beginning 
to be appreciated that chronic alcoholism itself is probably due to a 
mental defect, so that in a certain number of these cases of insanity 
and crime, the over-indulgence in alcohol must probably be considered 
a symptom and not a cause. Attempts have been made of late years 
to demonstrate that the effects of alcohol are hereditary, that the chil- 
dren of alcoholists supply a larger proportion of cases of insanity and 
crime than those of the rest of the population. The belief is widely 
entertained among biologists, however, that acquired characters such 
as alcoholism are not inherited directly, but can only affect the nutri- 
tion of the offspring. It would seem more probable, then, that the 
alcoholic excesses of the parent have no direct effect on the offspring, 
except in their nutrition at birth, but that the mental defect which 
leads to alcoholic excess in the one generation is inherited and 
leads to crime or insanity in the next. The deleterious effect of the 
alcoholic habit in the parent on the nutrition of the offspring is a w 7 ell- 
established fact. It has been shown experimentally by Hodge, who 
states that only a small percentage of the puppies born of parents 
treated with alcohol survive, and further that they are peculiarly liable 
to infectious disease, such as distemper. 

The treatment of acute alcoholic intoxication is to evacuate the stom- 
ach by means of the soft elastic tube. The patient ought to be put in 
bed and kept warm, as there is a tendency to a marked fall in the 
body temperature. In case of great congestion of the brain, cold may 
be applied in the form of ice-bags to the head, and some authorities 
recommend bleeding. In cases of extremely deep unconsciousness, 



ALCOHOL. 153 

nervous stimulants, such as caffeine or strychnine, may be had recourse 
to, and, as a last resort, artificial respiration. 

Chronic alcoholism is to be treated by the withdrawal of the poison, 
and this is best done gradually, as the immediate stoppage may lead to 
delirium tremens. It is often necessary to incarcerate the patient iu 
some retreat. A large number of drugs have been advocated in these 
cases, some of them such as opium acting as substitutes for alcohol, 
others (capsicum) replacing the local action on the stomach. The use 
of opium and other narcotics may however lead to a craving for these 
which is quite as serious as the original condition. Another method 
of treatment, which appears to be successful in some cases, is the ad- 
dition of nauseating drugs such as ipecacuanha or apomorphine to the 
alcohol which is supplied to the patient. The association of nausea 
with liquor eventually becomes so strong that alcohol in any form 
becomes distasteful. The organic lesions must be treated individ- 
ually. 

The treatment of delirium tremens generally consists in the use of 
chloral or opium to lessen the excitement. It is often necessary, or at 
any rate advisable, in these cases to allow small quantities of alcohol, 
as the sudden withdrawal may aggravate the condition. 

Bibliography. 

Binz, Jakseh. Verhandl. des VII. Congress f. innere Medicin, 1888, pp. 70, 86. 

Bunge. Die Alkoholfrage, Leipzig, 1887. 

Baratynsky. Arch, des Scienc. biolog. , iii. , p. 167. 

Jacquet. Die Stellungsnahme des Arztes zur Abstinenzfrage, Basel, 1896. 

Geppsrt. Arch. f. exp. Path. u. Pharm., xxii., p. 367. 

Miess. Ztschr. f. klin. Med., ii., p. 1. 

Bodldnder. Pfliiger's Arch., xxxii., p. 398. 

Martin and Stevens. Studies from Johns Hopkins Biological Laboratory, ii., p. 477. 

Pohl. Arch. f. exp. Path. u. Pharm., xxxi., p. 281. 

Riegel. Deutsch. Arch. f. klin. Med., xii., p. 79. 

Vas. Arch. f. exp. Path. u. Pharm., xxxiii., p. 141. 

Berkeley. Brain, xviii., p. 473. 

Brandt, Scanzoni, Farnsteiner. Ztschr. f. Biol., xxix. , p. 277; xxxiii., pp. 462, 
475. 

Buchner. Deutsch. Arch. f. klin. Med., xxix., p. 537. 

Chittenden and Mendel. Amer. Journ. of the Med. Sciences, 1896, p. 35. 

Sternberg. Arch. f. exp. Path. u. Pharm., x., p. 356. 

Kraepelin. Ueber die Beeinflussung einfacher psychischer VorgJinge durch einige 
Arzneimittel, Jena, 1892. And (with his pupils) in Kraepelin' s Psychologische Arbei- 
ten, i.-iv., passim. 

Jacqiiet. Arch, de Pharmacodynamique, ii., p. 107. 

Wihnanns. Pfliiger's Arch., lxvi., p. 167. 

Afanassijew. Zeigler's Beitrage, viii., p. 443. 

Kafdden. Ziegler's Beitrage, ix., p. 349. 

Martens. Arch. d. Pharmacodynamique, ii., p. 127. 

NdeJee. Deutsch. Arch. f. klin. Med., xxv., p. 416. (Delirium tremens.) 

Bner. Arch. f. [Anat. u.] Phys., 1898, p. 283. 

Liepmann. Arch. f. Psychiatrie, xxvii., p. 172. 

Gudden. Ibid., xxviii., p. 643. 

Radzikowski. Pfliiger's Arch., lxxxiv., p. 513. 

Spiro. Munch, med. Woch., 1901, p. 1871. 

Boedecker. Arch. f. Psychiatrie, xxvii., p. 810. 

Chittenden, Mendel and Jackson. Amer. Journ. of Physiol., i., p. 164. 

Zuntz and Magnus-Levy. Pfliiger's Arch., xlix., p. 438; liii., j>. 544. 

Dehio. Centralbl. f. Nervenheilkunde uud Psychiatrie, 1895, ]>. 113. 



154 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

Stewart. Journ. of Exp. Med., i., p. 623. Araer. Journ. of Physiol., i., p. 40. 
Kleefeld. Journ. de Physiol., iii., p. 563. 
Simanowsky and Sehoumoff. PfUiger's Arch., xxxiii., p. 251. 
Dieballa. Arch. f. exp. Path. u. Pharm., xxxiv., p. 154. 
Weissenfeld. Pliiiger's Archiv, lxxi., p. 60. 
Wendelstadt. Ibid., lxxvi. , p. 223. 
Guillery. Ibid., lxxvii., p. 321. 

Singer. Arch, internat. de Pharmacodyn., vi., p. 493. 
Schumberg. Arch. f. [Anat. u.] Phys.,"l899, Suppl., p. 289. 
Scheffer. Arch. f. exp. Path. u. Pharm., xliv., p. 24. 
Minervini. Ztschr. f. Hyg., xxix., p. 117. 
Rosemann. Pfliiger's Arch., lxxvii., p. 405 ; lxxxvi., p. 307. 
Neumann. Arch. f. Hyg., xxxvi., p. 1 ; xli., p. 85. 
Grehant. Journ. de l'Anatomie, xxxvi., p. 143. 
Abbott. Journ. of Exp. Med., L, p. 447. 

Laitinen. Ztschr. f. Hygiene, xxxiv., p. 206. Acta Societat. Scient. Fennic, xxix., 
No. 7. 

Birch- Hirschf eld. Arch. f. Ophthalmologic, lii., p. 358. 

Atwater and Benedict. U. S. Dept. of Agriculture Exper. Station Bulletin No. 69. 

Paton and Eason. Journ. of Physiol., xxvi., p. 166. 

2. General Anaesthetics — Ether and Chloroform. 

The term general anaesthetics is employed to indicate substances used 
to produce unconsciousness sufficiently complete to allow of surgical 
operations being performed. In the history of medicine there are 
repeatedly obscure allusions to substances used for this purpose, but it 
was not until the end of the first half of the nineteenth century that the 
era of surgical anaesthesia really opened. In 1798, Davy advised the 
use of nitrous oxide as an anaesthetic, but no practical use was made of 
his suggestion, and Wells may be said to have rediscovered this property 
of the gas in 1844, though his efforts to introduce it into general use 
met with no greater success than Davy's. Long used ether in 1842- 
1843 in surgical operations, but did not give any publicity to his dis- 
covery, and the honor of demonstrating publicly the practical use of 
ether in surgery must be awarded to Jackson and Morton in 1846. In 
1847, Simpson introduced chloroform to the medical profession as a 
substitute for ether, over which he supposed it to possess several ad- 
vantages. Its pharmacological action had been investigated some 
months earlier by Flourens, but Simpson appears to have made his 
investigations quite independently. Chloroform soon ousted ether in 
popular favor in Europe, and although in America a considerable 
number of surgeons continued to use it, ether had practically fallen 
into complete disuse throughout Europe, save in Lyons, until a few 
years ago. The continually increasing number of accidents in chloro- 
form anaesthesia has, however, caused a reaction to set in in favor of 
ether, and it seems probable that it will once more be reinstated as the 
rival, and perhaps as the superior, of chloroform throughout the world. 
Even in 1880, however, Kappeler could write that in Germany chlo- 
roform was used exclusively. 

Many attempts have been made to introduce other substances of the 
methane series as substitutes for the two generally recognized anaes- 
thetics, but as yet no other has attained popular favor. Soon after the 
introduction of ether and chloroform, nitrous oxide gained a perma- 
nent footing as an anaesthetic for short operations. 



ETHER AND CHLOROFORM. 155 

These anaesthetics are invariably given by inhalation and not by the 
stomach, as it is found that the exact depth of the narcosis can be 
much more easily controlled by the former method. Both the absorp- 
tion and excretion of these drugs occur almost entirely by the lungs, 
according to the ordinary physical laws of the absorption of gases by 
fluids. The more concentrated the vapor of chloroform in the lungs, 
the greater is the quantity absorbed into the blood and the deeper the 
narcosis. By regulating the proportion of the vapors in the air in- 
haled, therefore, an anaesthesia of any desired depth may be induced. 
The degree of narcosis and of danger is not indicated by the actual 
amount of the anaesthetic which has been used, but by the concentra- 
tion of the vapors which have been inhaled ; one patient may, in 
the course of a long operation, inhale and again exhale many ounces 
of chloroform without danger, while another may be thrown into a 
position of extreme peril by the inhalation of a few drops of chloro- 
form in concentrated vapor. 

Symptoms. — The action of chloroform and ether may be divided 
into three stages : 1 , that of imperfect consciousness ; 2, that of ex- 
citement ; 3, that of anaesthesia. 

The first effect of their application is a feeling of asphyxia, which is 
especially marked in the case of ether, and of warmth of the face and 
head and eventually of the whole body. The senses become less acute, 
the patient seeming to see only through a veil of mist, and the voices 
of those in the immediate neighborhood appearing to come from a dis- 
tance. Ringing, hissing and roaring in the ears, and a feeling of stiff- 
ness and of inability to move the limbs herald the approach of uncon- 
sciousness. With the exception of the first feeling of suffocation, the 
sensations are generally pleasant. During this stage the face is gener- 
ally flushed, the pupils enlarged, the pulse is somewhat accelerated, 
and the respiration may be rendered irregular by the sense of suffoca- 
tion, or may be slightly quickened. Even at this early stage sen- 
sation is blunted. 

The second stage of excitement varies extremely in different indi- 
viduals. In some cases, especially in children, it is entirely absent, 
and in others its presence may be indicated merely by tremor, by the 
stretching of the limbs, or by irregularities in the respiration, but in 
the majority of cases of anaesthesia it is much more marked. It often 
begins by movements of the arms, designed either to push away the 
inhalation mask or to enable the patient to rise ; soon his other mus- 
cles are involved in the movement ; he struggles, shouts, sings, groans, 
or bursts into laughter. The movements are not generally uncoor- 
dinated, but are evidently the result of some dream-like condition of 
the consciousness, and these dreams are often connected with the opera- 
lion or with the surroundings of the patient before the inhalation began. 
They are, of course, determined largely by his natural mode of thought 
— one person prays aloud and sings hymns ; another abuses the surgeon, 
the hospital and all his recent surroundings, while yet another is overcome 
with the fear of impending death and laments his unfortunate position. 



156 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

In this stage the pulse is generally quickened, the skin is flushed and 
often cyanotic, the respiration is extremely irregular from the strug- 
gling, and the pupil continues somewhat dilated. If the anaesthetic 
be pushed, however, the movements soon become less powerful, the 
muscles relax and the stage of anaesthesia sets in. 

In the third stage, the face assumes a calm, death-like appearance 
from the relaxation of the muscles, the pupils contract somewhat and 
do not react to light. The reflexes disappear, one of the last to go 
being the closure of the eyelids on touching the cornea. The pulse 
is generally somewhat slow and weak ; the face is pale in chloro- 
form anaesthesia, but may be suffused and cyanotic after ether. The 
respiration is slow and shallow, but regular. This stage of anaesthesia 
may be kept up for hours without much change by the repeated inha- 
lation of small quantities, although the pulse tends to become weaker 
and the respiration shallower unless the greatest care be exercised, and 
the body temperature invariably sinks. When the administration 
ceases, the patient passes again through the excitement stage, which, 
however, is not generally as violent, although it may be more pro- 
longed, and then often sinks into sleep, which lasts several hours. 
Not infrequently, however, instead of sleep, nausea, giddiness and vom- 
iting continue for some time after the recovery of consciousness. 

In surgical ansesthesia, the third stage is often interrupted by short 
intervals of semi-consciousness and slight excitement if the adminis- 
tration of the drug be occasionally interrupted, as is sometimes ad- 
visable in prolonged operations. 

The use of these drugs is so widespread, and the indications of 
danger in anaesthesia are so important that a more detailed account of 
the alterations observed during their use in the human subject may 
be inserted here. 

The pulse is often somewhat accelerated before anaesthesia, owing to 
the anxiety and nervousness of the patient, and in the first, and still 
more the second stage, a further acceleration may occur from the same 
cause, although in other instances marked slowing of the pulse may 
set in here from reflex stimulation. When the stage of anaesthesia is 
reached, the pulse becomes slower and weaker than normally, and this 
change increases with the depth of the anaesthesia produced. It re- 
mains perfectly regular, however, in ordinary cases, and, in fact, un- 
less the anaesthesia has reached an extremely dangerous stage. In 
very prolonged, deep anaesthesia the weakness of the pulse may give 
rise to anxiety, especially if the temperature of the body is very low. 

The respiration is generally fairly regular until the second stage, 
save that the breath may be held for some time owing to the choking 
sensation, and a deep gasp may follow ; coughing is occasionally met 
with, especially in the first stage of ether anaesthesia. In the second 
stage, the respiration is extremely irregular when the excitement is 
violent. The respiratory muscles are involved in the general convul- 
sive movements, so that no air whatever can enter the lungs for 
several moments, and then several deep gasps may follow and load 



ETHER AND CHLOROFORM. 157 

the blood with concentrated vapor. During the third stage the res- 
piration becomes regular but shallower and slower than before the 
anaesthetic was applied, and if the operation be prolonged, the weak- 
ness of the respiration may give rise to alarm. Large quantities of 
saliva and mucus may hinder the respiration and require removal, and 
a common occurrence is the production of snoring from the falling back 
of the tongue, and this may also require attention. 

The behavior of the pupil is of some importance in anaesthesia. 
During the first and second stages it is generally somewhat dilated, 
but as soon as complete unconsciousness is attained, it becomes rather 
narrower than it is normally. As the patient recovers, the slight dil- 
atation recurs, and if the respiration and circulation be dangerously 
weak, this dilatation also occurs in most cases. Dilatation of the pupil 
in the stage of anaesthesia, therefore, indicates danger, unless it is 
accompanied by symptoms of returning consciousness, such as reflex 
movements and vomiting. 

Other eye symptoms which occur in some cases are squinting and 
more or less rhythmic movements of the eyeball. In the beginning of 
the narcosis the pupil is generally directed upward and is covered by 
the upper lid as in ordinary sleep, but later it returns to the normal 
position ; curious rolling movements, which are quite independent in 
the two eyes, often make their appearance (Kappeler, Hogyes). 

The hypersecretion of saliva and of bronchial mucus is much more 
marked in ether than in chloroform anaesthesia. Vomiting occurs so 
frequently during anaesthesia that it may be looked upon rather as one 
of the attendant phenomena than as an accident. It may set in prac- 
tically at any time, but is more often seen in the late than the early 
stages, and more frequently when the anaesthetic is applied soon after 
a meal than when the stomach is empty. 

Action. — The action of ether and chloroform on the Central Nervous 
System is evidently similar to that of alcohol, although the phenomena 
habitually elicited in the use of the former are very rarely produced by 
the latter. In all three intoxications, however, there may be observed 
the stages of lessened consciousness, of excitement, and of total uncon- 
sciousness. Alcohol was formerly administered in very large quantities 
to allow of surgical procedure, and ether has not infrequently been used 
as a habitual intoxicant. 

These anaesthetics produce the same progressive paralysis of the cen- 
tral nervous system as alcohol, commencing with the highest cerebral 
functions, those of self-control, and passing downwards through the 
lower intracranial divisions. The spinal cord is affected before the 
medullary centres, which are the last part of the central nervous sys- 
tem to become paralyzed. Some authorities believe that the motor 
areas of the brain are first stimulated before being paralyzed, but it is 
unnecessary to enter upon this question here, as it has been discussed 
under alcohol. The wilder excitement of chloroform and other may 
be due to the greater irritation which they excite in the periphery. 
It may be remarked that the depression of the motor areas has been 



158 



ORGANIC DRUGS ACTING AFTER ABSORPTION. 



shown experimentally in the case of chloroform and ether, a much 
stronger electric stimulus being necessary to produce movement of a 
limb after these drugs than before them ; their excitability by the elec- 
tric current has not been tested, however, during the excitement stage. 
The anaesthesia is not produced equally rapidly throughout the body, 

the back and the extremities first be- 
coming insensible, then the genital or- 
gans and rectum and, last of all, the 
parts supplied by the trigeminus. The 
reflexes of the spinal cord are said to 
be first increased by ether and chloro- 
form and then depressed and paralyzed, 
but the primary increase is of very short 
duration and, in fact, it is open to ques- 
tion whether it occurs at all. It would 
seem that ether and chloroform tend to 
depress the sensory functions before the 
motor. For Bernstein found in some 
cases that if chloroform were excluded 
from a section of the spinal cord by 
destruction of part of the pia mater, 
reflexes could be elicited in other parts 
of the cord by the irritation of sensory 
nerves whose cells lay in the protected 
area, while irritation of nerves, the 
cells of which were exposed to the 
chloroform, had no effect (Fig. 5). In 
the protected area there were, of course, 
both motor and sensory cells, and an im- 
pulse reaching the protected sensory 
cell was transmitted to the neighboring 
and also to more distant motor cells. 
An impulse reaching the exposed sen- 
sory cell, on the other hand, was not 
transmitted to the motor cells, although 
these were shown by the first part of 
the experiment to be capable of stimula- 
tion. Later, however, the motor cells 
are also paralyzed, as is shown by 
stimulation of the cord having no effect, 

F, Fin the unaffected area, or by F', F' ___._„ „ T V, „ +U vocr^-rafi'/-»r. i'o cfill oMi^ro. 

in the poisoned area. The cells of the an- even WUen tUe respiration IS Still active. 

terior horns F, F' and the dendrites sur- Tripprvipal srirn nlfltinn of thp oe>rf>hrs\] 

rounding them are, therefore, intact after -Electrical Stimulation OI tne CereDrai 

the reflex arc is interrupted at some other mo t r areas produces movement for SOme 
point. . • i i 11 

time after sensation has been lost, but as 
the anaesthesia becomes deeper, their irritability disappears. Finally 
the medullary centres are also paralyzed by the anaesthetic. Some 
authorities have stated that they are first stimulated directly by chloro- 
form and ether, but the evidences for this will be discussed later (page 




Diagram of the spinal cord. A -B part 
of the cord exposed to the action of chlo- 
roform, B-C part unaffected. A sensory- 
impression traveling by the posterior root 
fibre D does not elicit a reflex movement, 
hut one reaching the cord through the un- 
affected root F causes reflex impulses, 
which may be sent out by the motor cells 
the unaffected area, or by F', F' 



ETHER AND CHLOROFORM. 159 

162). The medullary centres are liable to be affected by reflex stimu- 
lation up to the moment at which they cease to send out impulses, for 
the respiratory centre responds to stimulation of the superior laryn- 
geal nerve as long as the respiration continues. It is possible that the 
motor cells are not directly paralyzed by the drug, but can only send 
out impulses received from the sensory cells, and that the paralysis of 
these is the cause of the asphyxia. 

Shortly stated, the direct action of chloroform and ether on the cen- 
tral nervous system is a descending depression and paralysis which 
aifects the medullary centres last of all, and which probably affects the 
sensory and receptive functions sooner than the motor ones. 

The action of chloroform and ether on the Respiratory Centre is 
partly direct and partly indirect. In the first stage, the respiratory 
movements may be slowed or stopped temporarily by a reflex action 
set up by the irritation of the terminations of the trigeminus in the 
nose and throat and of the pneumogastric in the larynx and bronchi, 
but this interruption is only of short duration (Fig. 6). During the 



Fig. 6. 




Tracings of the blood-pressure (upper) and of the respiration (lower) of a cat at the beginning of 
ether inhalation. A, normal respiration. At B, ether inhaled, and there follows an immediate slow- 
ing of the respiration (reflex inhibition) culminating in gasping at C. The respiratory traciug then 
resumes its normal appearance except for some slowing (central). 

second stage the respiration is often rendered irregular by the convul- 
sive struggling, which produces alternately periods of asphyxia and 
deep gasping movements. Daring the third stage, the respiration is 
regular and no reflex disturbance occurs, because the sensibility is so 
dulled that the continued irritatiou of the nerve ends causes no reflex 
response. In this stage, however, the direct action of the drug on the 
centre makes itself manifest in the slow and shallow respiratory move- 
ments. If the drug be pushed, the weakness and slowness of the 
movements increase, until the respiration ceases entirely from paralysis 
of the centre. In man and the dog and cat the respiration is gradually 
extinguished, but in the rabbit the final standstill is preceded by very 
rapid and extensive respiratory movements, which have not been ex- 
plained hitherto, but probably bear some relation to the acceleration 
of the respiration seen in the rabbit after alcohol. 

The effects of the anaesthetics on the Circulation are complicated by 
the respiratory action, and in order to arrive at any satisfactory con- 
clusions as to the changes in the heart and vessels, it is therefore neces- 
sary to examine their action while the aeration of the blood is carried 
on artificially, when the effects are seen to be partly direct and partly 
indirect. The first change observed in the blood-pressure tracing, 



160 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

after chloroform or ether is often a slowing or even a temporary stand- 
still of the heart, due to reflex stimulation of the inhibitory centre 
from the irritation of the air passages ; but in other cases a short rise 
in the blood-pressure is seen from a similar reflex action on the vaso- 
motor centre and this may be accompanied by extreme acceleration of 
the pulse arising from the general excitement. Later, however, a fall 

Fig. 7. 



t ^^^ ,m ^* 



rtj-LTLTLrLrlrLrLrtj- UtrtjLrLrtrUUUArLr JlArtjlHrtJlrLOArt. 



jin 



^^J^JlJ^lArijuvrm^^ 



Gradual fall of the blood-pressure in a cat during anaesthesia with dilute chloroform vapor. At A, 
normal pressure. B, inhalation commenced and the pressure slowly falls soon afterwards. C, blood- 
pressure 5 minutes after B. D, 10 minutes after B. E, 13% minutes later. At E, the respiration 
has ceased, but the blood-pressure is still fairly high and the pulse is satisfactory. Below the time is 
marked in seconds. 

in blood-pressure is observed, and afterwards a distinct slowing of the 
heart. Eventually, if the administration be carried far enough, the 
blood-pressure falls to zero and the heart ceases to beat. The way in 
which this fall in the blood-pressure is produced has been the subject 
of prolonged discussion, but it is now generally recognized that the 
weakness of the heart is the chief factor and that along with this there 

Fig. 8. 




Sudden and dangerous fall in the blood-pressure from the inhalation of too concentrated vapor of 
chloroform during'ansesthesia in a cat. At A the concentrated vapor began to be inspired. At B the 
blood-pressure had fallen to about one third of the height at A, and the pulse was so weak as to be 
scarcely perceptible. The chloroform mask was removed, and at C artificial respiration was com- 
menced when the pulse rapidly improved in strength and the pressure began to rise. 

is a progressive enfeeblement of the vaso-constrictor centre. The 
vagus centre is much less affected, and in some instances the slowing 
of the pulse is due in part to its increased activity, so that more chloro- 
form may accelerate the pulse somewhat through the depression of the 
inhibition counterbalancing the direct deleterious effects on the heart. 
It is not infrequently asserted that the action of ether differs altogether 
from that of chloroform as far as the circulation is concerned, but this 



ETHER AND CHLOROFORM. 



161 



is erroneous. Chloroform acts much more powerfully than ether on 
the circulation, but their action is the same in kind. 

The frog's Heart under chloroform or ether beats more slowly and 
more weakly, and at the same time undergoes a certain amount of 
dilatation, all owing to the paralyzing effects of these drugs on the 
cardiac muscle. About 48 times as much ether as chloroform is re- 
quired to affect the frog's heart, however, and in order to bring it to 
diastolic standstill 36 times as much ether as chloroform must be 
added to the blood. 

The effects on the mammalian heart in deep anaesthesia are very 
similar. The slowing is not so marked, however, as the weakness and 
the dilatation, so that the rhythm of the pulse does not indicate the 
extent to which the heart is affected. The auricles are acted on by 
smaller quantities than the ventricles, and the former may be rendered 
so weak as to give practically no movement to an attached lever long 



Fig. 9. 




Myocardiographic record of the movements of the right auricle (upper tracing) and right ventricle 
(lower tracing) of the dog during the inhalation of concentrated chloroform vapor. During systole 
the lever attached to the auricle moves from D' to S', that attached to the ventricle from D to S. In 
diastole they return to D' and D respectively. At A, concentrated chloroform was inhaled. The ex- 
cursion of the levers towards systole rapidly diminished, while that of the ventricle towards D was 
somewhat augmented. After a short time the auricle ceased in diastole, while the ventricle con- 
tinued to beat, though much weakened. At B, the chloroform was shut off and the heart began to 
recover very soon afterwards. 



before the ventricular force is very seriously impaired (Fig. 9). The 
first direct effect of these drugs on the heart, therefore, is a weakness 
in the auricular contraction and an increase in the ventricular relaxa- 
tion. The diminution in the strength of the auricle progresses rapidly, 
while the ventricular dilatation soon reaches a maximum and is ac- 
companied by lessened force of contraction. The auricular weakness 
soon becomes so great that practically no blood is expelled by its 
systole, and the slowing of the heart, which has not been very marked 
up to this point, becomes distinct. The ventricular contractions next 
become extremely weak and occasionally fail entirely, and soon after- 
wards the heart comes to a standstill in diastole. Occasionally a venous 
pulse appears during surgical anaesthesia, and this may be due to the 
dilatation of the right ventricle causing incompetency of the tricuspid 
11 



162 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

valve. Stimulation of the inhibitory nerves has less effect than usual 
during anaesthesia with chloroform or ether, but it does not seem likely 
that this lessened activity of the peripheral mechanism plays any part 
in the symptoms observed in practice. 

The Vascular effects of the anaesthetics are rendered very difficult 
of investigation by the presence of these changes in the heart. The 
general impression has been that the tone of the vaso-motor centre is 
lowered and that the blood-pressure therefore falls through the dila- 
tation of the vessels along with the weakness of the heart. Thus 
Scheinesson observed marked dilatation of the vessels of the rabbit's 
ear under chloroform, and several investigators found the reflex irrita- 
bility of the vaso-motor centre diminished or abolished entirely by 
chloroform, while ether had less effect on it. 

Gaskell and Shore, however, came to the result that chloroform actually 
stimulates the vaso-motor centre and causes narrowing of the peripheral 
vessels. Their most important experiments consisted in feeding the brain 
of one rabbit or dog from the vessels of another (Fig. 10) by joining the 
peripheral ends of the carotids, C, in one animal, A, to the central 
ends, C, in the other, B. The jugular veins, J J', were connected in the 
same way. On giving chloroform to the feeder rabbit, B, its blood-pressure 
fell, because it was carried to the heart, while on the other hand, the blood- 
pressure of the other rabbit, A, rose, although chloroform was carried to its 
brain and vaso-motor centre. They conclude from this that the vaso-motor 
centre is stimulated, and the arterioles contract through the action of chloro- 
form, but that the resultant rise of blood-pressure is prevented by the simul- 
taneous weakening of the heart's action. After large quantities of chloro- 
form, however, the vaso-motor centre also becomes weakened and the 
arterioles dilate. Conclusions from so complicated a method can be drawn 
safely only when uniform results have been obtained in a large number of 
experiments, but it would seem that the effects of the anaesthetics on the 
vaso-motor centre have been exaggerated hitherto, and that the chief point 
of attack as regards the circulation is the heart. 

There is no reason to suppose that the vessels are acted on directly 
by either chloroform or ether, although it is not impossible that this is 
the case. A marked dilatation of the skin vessels occurs in the first 
stage of anaesthesia, and in the case of ether at any rate, generally 
persists throughout ; this is probably due to some central action, but 
here, as in many other similar instances, the primary dilatation of the 
cutaneous vessels has not been fully explained. 

During anaesthesia Pick found that the blood current in the veins 
of the extremities is slower than usual, while in the brain and abdo- 
men it is increased owing to the extreme dilatation of the vessels. 
Other observers mention anaemia of the brain as a constant feature in 
anaesthesia. It seems likely that this divergence of views is due to 
the observations hiving been made at different stages, and that the 
brain vessels are at first dilated like those of the skin, but afterwards 
become pale and anaemic. 

Kemp has recently drawn attention to a marked contraction of the 
renal vessels of the dog without a corresponding increase in the general 
blood-pressure during deep ether anaesthesia, which lessens the secre- 



ETHER AND CHLOROFORM. 



163 



tion of urine and may arrest it completely, or cause such injury to 
the kidney that albuminuria or even hematuria may follow. Some 
writers state that albumin is found in the urine in a considerable pro- 
portion of cases of ether anaesthesia in man, which would suggest that 
a corresponding action is elicited here, but others have failed to detect 
any change except a slight diminution of the urine. The discrepancy 
in these results may perhaps be due to the method of administration. 
Ether is often given in such a way as to induce partial asphyxia and 
this may induce contraction of the renal vessels without a correspond- 
ing rise in the blood-pressure if the heart be much weakened by the 

drug. 

Fig. 10. 




Diagram of the cross-circulation in two rabbits. C, C, the central and peripheral end-; of the 
carotid arteries connected by a tube. J', J, the peripheral and central ends of the jugular veins con- 
nected in the same way. The arrows iudicate the direction of the blood current to and from the brain 
of A. 



The Muscles and Nerves are not affected by chloroform or ether when in- 
haled, but when a frog's muscle is exposed to an atmosphere of either oi 
them, it is weakened, loses its irritability and eventually passes into rigor 
mortis ; Eisenmeyer and Buchheim found that the relaxation of muscle after 
contraction was somewhat retarded by exposure to dilute vapor oi' chloro- 



164 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

form. Waller has recently shown that when a frog's nerve is exposed -to 
chloroform or ether vapor in weak dilution, its irritability is at first increased ; 
strong vapor, on the other hand, abolishes the excitability temporarily in 
the case of ether, generally permanently in that of chloroform, which is 
much the more powerful nerve poison of the two. The sensory fibres are 
said to be paralyzed sooner than the motor when chloroform or ether is ap- 
plied to a mixed nerve (Pereles and Sachs). When the sciatic nerve of a 
frog is dipped in ether solution and then stimulated, it is often found that 
the flexor muscles contract while the extensors remain flaccid, while in the 
normal animal exactly the opposite occurs. A somewhat similar result is 
got on stimulating the recurrent laryngeal nerve of the dog in deep ether 
narcosis. This puzzling observation has been explained by Albanese as 
being due to the nerve fibres to the extensor muscles lying more superficially 
than the others, and thus being acted on sooner by the anaesthetic. The 
local paralyzing effects of ether have been elicited repeatedly in the human 
subject by its subcutaneous injection, and have occasionally been followed 
by neuritis and permanent weakness. 

Chloroform and ether dissolve the Red Corpuscles and free the 
hemoglobin when they are shaken with defibrinated blood outside the 
body, and chloroform is said to retard the reduction of oxyhemoglobin 
by forming a loose combination with it ; Da Costa holds that ether 
tends to destroy the red cells during anaesthesia and advises caution in 
its administration in cases in which a diminution in their numbers may 
be of serious import. Apparently chloroform, when absorbed, exists 
not in simple solution but in combination with the cholesterin and 
lecithin of the red corpuscles. 

The effects of chloroform and ether on the Pupil present some varia- 
tion in different animals, and, indeed, are not very constant in man. 
No entirely satisfactory explanation of their mechanism has been 
offered as yet. The dilatation of the pupils in the first and second stages 
is merely the accompaniment of the general excitement and anxiety, and 
is not specific. The contraction in the stage of unconsciousness is similar 
to that seen in natural sleep, and is evidently of central origin. It may 
perhaps be a secondary effect of the dilatation of the vessels in the iris 
(Limbourg). The dilatation occurring during wakening or vomiting 
is evidently caused by the same process as that of the preliminary 
stages. Just before death the pupil dilates, and this may perhaps be 
attributed to the effects of asphyxia on the muscle of the iris, and is 
so frequently observed in death from other causes that it cannot be 
regarded as a direct result of the chloroform. 

The movements of the eye occasionally seen during anesthesia have 
not been explained. The dissociation of the movements is believed by 
ITogyes to indicate a preliminary stimulation and subsequent exhaus- 
tion of the centres for their coordination, but this explanation conflicts 
with the general depressant action. 

The local effects of the anesthetics on the Alimentary Canal and 
Respiratory Passages are confined to irritation with resultant reflexes. 
Thus the profuse secretion of saliva and of mucus is due to the irri- 
tation causing increased activity of the glands reflexly, and can be 
arrested by atropine. It has been stated that the bronchial rhonchi 



ETHER AND CHLOROFORM. 165 

are due entirely to aspirated saliva, but this is incorrect, as they occur 
in animals to which the anaesthetic has been given through a tracheal 
canula. The irritation is much greater when concentrated ether fumes 
are inhaled than in ordinary chloroform anaesthesia. 

This local irritation may explain in part the vomiting which is so 
often a feature of anaesthesia. The irritant vapors reach not only the 
throat, but also the stomach with the mucus swallowed, and irritation 
of either of these parts may well lead to reflex vomiting. But similar 
effects are occasionally induced by other methods of anaesthesia, such 
as by nitrous oxide, in which local irritation can play no part, so that 
there is probably some central effect in addition. The ordinary move- 
ments of the stomach and intestine do not seem to be influenced by 
anaesthesia, unless when it is accompanied by asphyxia, when the peri- 
stalsis may be increased. 

The Kidney appears to be affected in a certain proportion of cases 
of anaesthesia in man as is shown by the appearance of albumin in the 
urine. Chloroform induces typical fatty degeneration occasionally, 
while the albuminuria after ether has been ascribed to a specific vas- 
cular change by Kemp. The proportion of cases in which this organ 
is affected seems to vary extraordinarily, some authorities finding albu- 
minuria in 30 per cent, of the cases where chloroform was used ; 
while others could detect it in less than 8 per cent. Most surgeons 
consider chloroform far more deleterious to the kidney than ether. 

The Uterine Contractions during parturition seem little influenced by 
moderate anaesthesia, but are slowed in the deeper stages, probably 
because the anaesthetics lessen the irritability of the spinal cord. 
Chloroform and ether pass into the foetal blood, and some experi- 
ments are recorded in which the foetus was killed by the inhalation, 
while the mother recovered. This may be caused either by the direct 
action of *the drug on the young animal, or by the low maternal blood- 
pressure leading to its asphyxia. It does not seem dangerous to in- 
duce a moderate degree of anaesthesia during labor in human beings, 
although here, too, the effects on the child are shown by an increase in 
the nitrogen excretion in the urine for some days. 

The Temperature falls during anaesthesia of even short duration. 
Thus Kappeler found it reduced 0.2-1.1° C. when chloroform was in- 
haled 15-40 minutes, and a fall of 3-5° C. has been observed during 
very long anaesthesia. This action is due partly to the greater output 
of heat through the dilated skin vessels, but mainly to a lessened heat 
production from the diminished muscular movement. It is not neces- 
sary to assume, therefore, as some writers do, that the anaesthetics lessen 
the heat production by their direct effects on the tissues in general. 

Of late years a good deal of interest has been manifested in the 
effects of the anaesthetics on the Metabolism of the tissues, and it is now 
generally recognized that chloroform, in addition to its action on the 
central nervous system, produces marked changes in the nutritive proc- 
esses of protoplasm. The simpler organisms, which are devoid of 
nervous structure, are killed in comparatively dilute solutions, and 



1G6 ORGANIC DRUGS ACTING AFTER ABSORPTION 

chloroform water, therefore, prevents or retards putrefaction and the 
fermentation of yeasts. It seems to hinder the action of some fer- 
ments, such as pepsin and rennet ferment, when added in comparatively 
large quantities, but increases their activity in greater dilution. Plants 
cease to assimilate carbonic acid, but are not killed by chloroform 
except in very large quantities. In the higher animals and in man, 
evidences of an alteration in the processes of life and nutrition of the 
different organs have also been discovered, quite apart from the effects 
on the nervous system. Thus fatty degeneration l of various organs is 
produced by chloroform administered repeatedly and even by single 
inhalations in some cases. The organs implicated in this change are 
the liver, heart and kidneys more especially, but degeneration of ordi- 
nary muscle has also been observed occasionally. If this process 
attains a certain degree of development, it may lead to failure of the 
heart, but otherwise the tissues recover in the course of a few days. 
Traces of fatty degeneration have been observed after prolonged ether 
narcosis also, but they are so slight that no significance attaches to 
them from a practical point of view (Selbach). Given in small 
quantities for several months, chloroform leads to atrophic cirrhosis 
of the liver, and to a less extent of the kidneys, spleen and lungs, this 
cirrhotic change forming a sequel to a preliminary fatty degeneration 
of the parenchymatous cells. Some jaundice occasionally occurs after 
chloroform anaesthesia, and in one case acute yellow atrophy of the liver 
seemed to be induced by it. Ether has no such effect. (Bandler.) 

Other symptoms of disordered nutrition are obtained from the urine 
secreted during and after the administration of chloroform either by 
inhalation or by the stomach. The nitrogen eliminated is considerably 
increased, and the sulphur shows a similar augmentation, and these 
would seem to indicate an increased destruction of nitrogenous (pro- 
teid) bodies in the tissues. In the normal urine, the sulphur appears 
partly in the form of sulphates, partly in forms in which it has under- 
gone less complete oxidation. After chloroform the proportion of these 
constituents is changed, the unoxidized sulphur forming a much larger 
part of the total than normally, and apparently occurring in a substance 
nearly allied to cystin. (Kast and Mester.) This indicates that while 
the breaking up of the nitrogenous tissues is greater than normal, 
the oxidation is not so perfect, and another fact pointing in the same 
direction is the not infrequent occurrence of acetone in the urine and 
breath and of glycosuria. (Becker.) It has long been recognized that 
diabetes is liable to be aggravated by chloroform anaesthesia, and 
some fatalities after chloroform seem due to this action. The sugar 
of the blood has been found to be increased, and the glycogen of the 
liver is diminished or entirely absent after chloroform ; this is, ac- 
cording to Paton, the effect of a specific action on the liver cells, which 
form glycogen into sugar much more rapidly than usual ; ether has a 
very much less powerful action on them. Bile pigment is said to occur 

1 The same divergent views are held in regard to the nature of this " degeneration " 
as in the case of phosphorus, to the chapter on which the reader is referred. 



ETHER AND CHLOROFORM. 167 

in the urine in a considerable number of cases of anaesthesia with 
chloroform, especially one or two days after the administration. The 
uric acid of the urine is augmented. 

These effects of chloroform on the metabolism resemble very closely 
those of phosphorus poisoning, and have, like them, been ascribed to 
the formation of acid in excess in the tissues. They seem to occur 
only after those substances of the fatty series in which chlorine is sub- 
stituted, ether having little or no effect in producing fatty degeneration 
or in changing the proportion of the sulphur compounds in the urine. 

Distribution in the Body. — When chloroform or ether is absorbed 
from the lungs, it is carried all over the body by the blood, but is not 
equally distributed throughout the tissues. It has been mentioned 
already that a loose combination exists between chloroform and the 
lecithin and cholesterin of the red cells, and it was to be anticipated 
that those organs which are richer in these constituents would contain 
larger quantities of the drug. As a matter of fact, both chloroform 
and ether are found in larger quantities in the brain than in the blood, 
liver or muscles, which is in conformity with the theory of Meyer and 
Overton regarding the causation of narcosis (page 128). 

The Excretion of both ether and chloroform takes place mainly by 
the lungs. Whenever the partial pressure of the vapor in the alveoli 
falls sufficiently far below that in the blood to loosen the combination 
between the anaesthetics and the constituents of the blood, the drug 
diffuses back into the alveoli, and thence passes into the air. Most of 
the anaesthetic is eliminated very rapidly, but traces of chloroform are 
said to be found in the breath for 24 hours after the inhalation and 
even longer in cases in which there is a tenacious mucous secretion from 
the bronchi. As far as is known this is the only way in which ether 
is excreted, but small quantities of chloroform escape by other channels, 
for it has been found in the urine, and is said to occur in the perspira- 
tion and the milk. Some of the chloroform inhaled seems to undergo 
combustion in the body, for Kast found the chlorides of the urine con- 
siderably increased after its inhalation. 1 The acidity of the urine is 
also augmented, owing to the hydrochloric acid formed by the com- 
bustion. Bongers has found traces of chloroform in the stomach after 
its subcutaneous injection. 

Differences Between Chloroform and Ether. — Ether and chloroform 
resemble each other closely in their general effects, but differ in certain 
points of importance. Thus ether has a much weaker narcotic action 
than chloroform, for Spenzer found that 1.5-2.5 volumes per cent, of 
ether vapor in air produced only incomplete anaesthesia, that 3—3.5 per 
cent, induced narcosis in 25, and 4.5 per cent, in 15 minutes, while (5 
per cent, stopped the respiration within ten minutes; Rosenfeld ob- 
tained no narcosis with 0.5-0.7 volume per cent, of chloroform, com- 
plete narcosis with 1 per cent, only after 30-45 minutes, and respira- 
tory standstill with 1.5 per cent, in the course of f— 2 hours after the 

*It is stated that chloroform in the course of its destruction forms traces of 
carbon monoxide, which may be recognized in the expired air. 



168 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

inhalation commenced. 1 So that chloroform is about .'3-3 J times as de- 
pressant to the central nervous system as ether, while, on the other hand, 
its action on the heart is 36—48 times as great as that of ether. Ether 
has to be given in more concentrated form to produce anaesthesia, and, 
therefore, produces more irritation of the air passages, as shown by the 
greater secretion of saliva and mucus, by coughing, and by the sensation 
of asphyxia. Dreser has shown, however, that if air containing less than 
6 per cent, of ether be inhaled, this irritation and feeling of suffocation 
is not very marked. Anaesthesia is produced with greater difficulty, 
more slowly and often less perfectly than with chloroform, and the 
stage of excitement is generally more violent and prolonged. But the 
pulse is not nearly so much affected as by chloroform ; it may be 
somewhat slower than usual, but is full and strong. The concentra- 
tion of chloroform w T hich is necessary to produce anaesthesia is very 
close to the concentration which causes serious impairment of the 
heart's action, while, on the other hand, 3J percent, ether vapor is suffi- 
cient to cause narcosis, but a very much stronger concentration is re- 
quired to cause a dangerous condition of the heart. In the same 
way the difference in the concentration required to produce anaes- 
thesia and that which will stop the respiration is very much smaller in 
chloroform than in ether, and the anaesthetist has thus more leeway 
when he uses the latter. The changes in the metabolism following 
the use of chloroform are not produced to the same extent, if at all, by 
ether. 

Regarding the Choice of an Anaesthetic it must be said that each has 
its advantages, but that ether is less liable to cause dangerous symp- 
toms than chloroform, and ought, therefore, to be used wherever special 
circumstances do not indicate the latter. Chloroform is always pre- 
ferred by the patient, for it causes less irritation and less feeling of suf- 
focation, and it is often preferred by the surgeon because it induces an- 
aesthesia sooner and less of it is required. In cases where excitement 
is to be avoided as much as possible, or in which a very deep anaesthesia 
with complete muscular relaxation is required, and in irritable condi- 
tions of the air passages, chloroform ought to be used rather than ether. 
In the case of drunkards, ether sometimes fails to induce deep anaesthe- 
sia, and in very hot climates anaesthesia with ether may be difficult and 
unpleasant to induce owing to its rapid evaporation, so that in these 
cases chloroform may be necessary. Lastly, where artificial lights are 
necessary (except the electric incandescent), or where the actual cautery 
is to be used, ether is dangerous on account of its inflammability, and 
chloroform is indicated. On the other hand, chloroform is specially con- 
traindicated in cases of fatty change of the heart and in renal disease. 
The disadvantages of both anaesthetics may often be avoided by in- 
ducing unconsciousness by chloroform and prolonging it by small 
quantities of ether. The effects of the prolonged use of chloroform 
are avoided in this way, and at the same, time the excitement is less 

1 Other investigators have found different absolute values from these, but the relative 
strength of ether and chloroform is generally held to be about 1 to 3. (Honigmann. ) 



ETHER AXD CHLOROFORM. 169 

marked, and less irritation of the air passages is elicited than if the 
anaesthesia had been induced by concentrated ether vapor. 

It has been found that anaesthesia either by chloroform or ether reduces 
the resistance offered by the organism to the invasion of pathogenic 
organisms. Thus normal frogs and rats possess a high degree of 
immunity to anthrax infection, but became susceptible to it if subjected 
to a short anaesthesia before inoculation. 

The Dangers of Anaesthesia are caused only in part by the direct 
action of the ether or chloroform, for fatal accidents have occurred 
from objects such as false teeth or tobacco plugs falling into the air 
passages and causing asphyxia, while vomited matter has been drawn 
into the larynx in some cases. Very often the relaxation of its 
muscles permits the tongue to fall back into the throat, rendering the 
breathing labored and stertorous ; this is at once relieved when the 
tongue is drawn forward. The accumulation of saliva and mucus, or 
blood in the throat may lead to similar symptoms. In these accidents 
the chloroform or ether is only indirectly the cause, but in a large and 
ever-increasing number of cases, the fatal effects must be ascribed to 
the direct action of the anaesthetics. The proportion of accidents during 
anaesthesia is very difficult to estimate, and great discrepancies occur in 
the statistics of different surgeons. Thus, in one of the London hos- 
pitals, one death occurred from chloroform in 1,236 cases of anaesthesia ; 
Juillard gives one in 3,258, McGuire one in 15,000, as the proportion 
of fatalities, while Lawrie gives a series of over 40,000 cases without 
a single death. A fair average would seem to be one death in 3,000 
chloroform inhalations. The statistics of ether fatalities also vary 
from one death in 3,000 to one in 16,000 cases, but probably one in 
10,000-12,000 cases would represent the average mortality. 1 

A very prolonged discussion as to the Cause of Death in these cases 
has been carried on, and even now there cannot be said to be any 
unanimity of opinion on the subject. A fatality may occur practically 
at any stage of the anaesthesia, and the accounts of its onset and symp- 
toms differ exceedingly. In the majority of cases it is stated that the 
pulse suddenly disappeared, and the breathing either ceased at the same 
moment or after one or two weak inspirations. In others the respi- 
ration is stated to have ceased before the pulse, and in several the 
heart beat could be felt or heard after the pulse ceased. The evidence 
of the practical anaesthetist is, however, of doubtful value, as an accident 
in anaesthesia demands prompt measures, and no great attention can be 
paid to the exact order in which the phenomena occur. In addition, 
there is a feeling that a certain amount of culpability attends a fatality 
due to the stoppage of the respiration, and a tendency exists conse- 
quently to ascribe it to heart failure when there is any uncertainty. 

Large series of experiments with chloroform have been carried out 
on animals with somewhat varying results. It was formerly stated 
that death might occur in the commencement of anaesthesia through 

■Grurlt's careful statistics of 330,000 cases of anesthesia gave a mortality of 1 in 
2,000 for chloroform and 1 in 5,000 for ether, but these both seem unusually high. 



170 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

reflex arrest of the heart or respiration from the irritant action of the 
vapor on the terminations of the sensory nerves in the nose and throat. 
This has now been disproved, and it is recognized by most authorities 
that death occurs only from the action of the drug after its absorption 
into the blood. The reflexes arising from the action of chloroform and 
ether on the respiratory passages are identical with those produced by 
the inhalation of ammonia or acetic acid, and fatalities do not occur 
from either of these. 

As to the exact way in which anaesthetics cause death after absorp- 
tion, a dispute has been carried on for many years. Until 1889, the 
general impression was that, while ether paralyzed the respiration with- 
out affecting the heart, chloroform acted first on the heart and para- 
lyzed it before the respiratory centre. Snow and others, however, 
maintained, in opposition to this, that chloroform caused death by par- 
alysis of the respiratory centre. In 1889, some criticisms by the Lan- 
cet of the results of experiments in Hyderabad led the Nizam (Prince) 
of that province to appoint a commission, including Sir Lauder Brun- 

Fig. 11. 



wmm ^m m 




_j^ r ^Mi|| 



D 

Tracings of the blood-pressure (upper) and of the respiration (lower) of the cat in the last stage of 
ether anaesthesia, failure of the respiration. At Jf the ether was shut off', aud at D artificial respira- 
tion was began. The oscillations on the respiratory tracings after D are due to the artificial respira- 
tion. The heart continues to beat after the failure of the respiration. The pulsations increase in 
size, not from an increase in the strength of the heart, but from the slowness of the beat, which gives 
time for the arteries to empty themselves between each pulse. 

ton, to investigate the question, and after experimenting on over 600 
animals, this commission came to the conclusion that death during 
chloroform inhalation is always due to arrest of the respiration. This 
decision has been subjected to much criticism, and it would seem that 
while it is literally true that the respiration is always carried on as 
long as the circulation, the alterations in the circulation produced by 
chloroform were not properly appreciated, or, at any rate, were not 
sufficiently emphasized in the report. The condition when the breath- 
ing fails varies with the concentration of the vapor. If very dilute 
chloroform or ether be inhaled, the respiration always ceases several 
minutes before the heart, which continues to beat fairly strongly at 
first but rapidly becomes weaker. If more concentrated vapor be 
used, the respiration again ceases before the heart, which is, however, 
much weakened and comes to a standstill after a short interval, and 
as the concentration is increased, the weakness of the heart at the mo- 
ment when the respiration fails, also increases, and the interval between 



ETHER AND CHLOROFORM. 171 

the arrest of the respiration and of the heart-beat becomes shorter. 
Finally, when air saturated with vapor is inhaled, the interval between 
the two is so short as to be inappreciable (Fig. 12). When concen- 
trated vapor of either chloroform or ether is inhaled, the pulse may 
be so weak as to be no longer perceptible before the respiration 
ceases, and the anaesthetist, therefore, believes that heart failure has 
been the cause of death, but if the movements of the heart be regis- 
tered directly, it is found beating as long as the respiratory movements 
are carried on. The importance of the condition of the heart is fur- 
ther shown by the results of attempts to resuscitate the animal after 
the respiration has ceased ; for if artificial respiration be commenced at 
once, the animal can invariably be restored to life, provided the heart 
has not been weakened too much ; but if concentrated vapors have 

Fig. 12. 




D 



D 



-. > 



E 



Diagram representing the state of the heart at the failure of respiration from an anaesthetic (chloro- 
form or ether). A represents the respiratory movements, which cease very early in the tracing, B 
the pulsations of the heart at this point if the anaesthetic vapor has been much di'luted with air, r? if 
it is of medium strength, D if very concentrated, and E if saturated. The heart pulsations are recorded 
by the mercury manometer. 

been inhaled, the heart is unable to carry on the circulation, and the 
animal cannot be resuscitated. 

Hill has recently stated that when concentrated vapor is inhaled, 
the heart may sometimes cease before the respiration, which is finally 
paralyzed in part by the direct action of the drug, but mainly by the 
anaemia caused by the foil of blood-pressure. But almost all the exact 
experiments of the last few years show that the respiration fails before 
the heart. It is quite true that the medullary centres may surfer from 
the anaemia as well as from the direct action of chloroform, but the 
heart always continues to beat as long as the breathing is maintained, 
and, save in exceptional circumstances, for some time longer. 

From a practical point of view, it is of comparatively little impor- 
tance wdiether there are a few fluttering beats of the heart after the 
last inspiration or not. The all -important question is whether the 
heart has been so injured as to be unable to carry on the circulation, 
and this is decided by the concentration of the vapor that has been in- 



172 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

haled. It has been mentioned already that ether aets very much less 
on the heart than chloroform, and this is really the reason why ether 
is so much the safer anaesthetic. Even when dilute vapor of chloro- 
form is inhaled, the heart is considerably injured when the respiration 
ceases, while unless very concentrated ether fumes be inhaled, the 
weakness of the heart is very much less. 

The autopsy in cases of death by chloroform or ether shows no spe- 
cific lesions. The blood is often dark colored from the asphyxia, and 
the heart is found dilated. Irritation of the respiratory passages may 
be present in ether poisoning, and the odor of the anaesthetic may be 
recognized in the different organs. Microscopic examination may 
show some alterations in the cells of the respiratory centre and cardiac 
ganglia, fragmentation of the heart muscle, and some degeneration of 
the liver, kidneys, spleen and heart after chloroform (Porosehin). 

Apparatus and Principles. — The principles on which the safe pro- 
duction of anaesthesia is based, then, are comparatively simple, but 
their interpretation into practice has given rise to various methods. 
A large number of inhalers have been introduced with the object 
of permitting of only a certain degree of concentration of the vapors. 
But the great majority of these are entirely erroneous in principle, 
the concentration of the vapor being determined by the character 
of the respiration of the patient, and the number of accidents has not 
been appreciably reduced by their use. In one of these, the amount 
of oxygen available for respiration was found to be reduced to 5 per 
<?,ent., while the carbonic acid had risen to 7.8 per cent, after two min- 
utes' respiration. This mixture of gases is insufficient to support the 
-combustion of a candle, and is very near that which is immediately 
fatal to animal life. In another the concentration of the vapor was 
found to vary between 1.2 and 16.4 volumes per cent. An apparatus 
has recently been constructed by Dreser on correct principles, which 
allows of an exact gradation in the strength of the vapor inhaled, but 
it is exceedingly cumbrous, and while it might be used in hospitals, is 
certainly not available for ordinary practice. The advantage of this 
principle of measuring the concentration of the vapors is further 
only relative, for it has been shown that vapors so dilute as to 
be absolutely safe do not induce anaesthesia within a reasonable 
time. Thus 1 per cent, chloroform seems to be absolutely safe, 
but no surgeon will wait J — f hr. for the anaesthetist. To induce 
anaesthesia, therefore, vapors have to be used, which would in time 
be fatal, and only after the reflexes disappear, is it possible to 
reduce the concentration to the point of absolute safety. The 
responsibility of the anaesthetist is, therefore, lessened, but by no 
means entirely removed by these methods. In the vast majority of 
cases, however, much simpler apparatus is used, and the ordinary mask 
or towel on which the anaesthetic is poured is not responsible for a 
larger proportion of accidents than the more complicated forms of ap- 
paratus. When no inhaler is used, the anaesthetist attempts to regulate 
the concentration of the vapor according to the symptoms, and this can 



ETHER AND CHLOROFORM 173 

be done with complete success by watching the respiration closely. If 
the breathing be shallow, much less concentrated vapor is inhaled into 
the alveoli than if it be deep and gasping, for in ordinary respiration 
the air in the smaller bronchioles and alveoli is not exchanged directly 
with every respiration, but only by a process of diffusion from the 
larger air passages. The deeper the respiration, however, the further 
does the vapor penetrate and the lower the concentration needed to 
change the quantity in the blood. An experienced anaesthetist, by 
watching the respiration, removing the mask during deep breathing 
and replacing it when it becomes steady, can regulate with sufficient 
nicety the concentration of the anaesthetic in the alveoli and thereby 
the quantity in the blood. When anaesthesia has been attained, he of 
course ceases the administration until the return of the reflexes indicates 
awakening consciousness, and even then applies much smaller quantities 
than were necessary at first. This method of inducing anaesthesia re- 
quires the anaesthetist to watch only the respiration and the reflexes, 
and is that advised by Simpson and his followers (see Hyderabad Com- 
mission Report). A further safeguard has been sought for in the con- 
dition of the pulse, and this would seem the natural consequence of 
what has been stated above as to the importance of the condition of 
the heart. The pulse, however, is not very reliable as a guide in 
anaesthesia, for in the second stage, in which a certain number of fatal- 
ities occur, it is quickened by the excitement and may be irregular, and 
only gives indications of danger when it is too late to take measures to 
prevent it. In the third stage it may become gradually weaker, and 
thus indicate approaching danger, but if the respiration be watched 
the warning is given earlier. A large number of anaesthetists advise, 
however, that pulse and respiration both be watched, and this would 
seem to be the safest method, provided always that the anaesthetist does 
not depend on the pulse too much for indications of danger, and does 
not allow it to distract his attention from the more important indica- 
tions given by the respiration. 

Preliminary Examination. — Before anaesthesia, a careful examination 
should be made of the condition of the patient, and if there is great 
anxiety and excitement, a hypodermic injection of morphine may be 
given beforehand, or chloral may be prescribed, but these are rarely 
necessary. Valvular disease of the heart does not contraindicate an 
anaesthetic unless there are marked symptoms of inefficiency, such as 
dropsy or oedema. In fatty disease of the heart, on the other hand, 
chloroform is to be avoided, and if it seems extensive, ether is also 
dangerous from the strain put on the circulation during the excitement. 
Chloroform is liable to induce fatty degeneration of the heart, and for 
this reason it would not seem advisable to use it in successive operations 
on the same patient. Atheromatous arteries are dangerous from the 
tendency to apoplexy during the second stage also, and if anaesthesia 
is absolutely necessary, an opiate ought to be given previously. Anaes- 
thesia is said to be dangerous in cases of brain tumor, and this may 
possibly arise from the fragility of the vessels. In cases of bronchitis 



174 ORGANIC DRUGS ACTING AFTER ABSORPTION 

and catarrh of the air passages, chloroform is to be preferred to ether 
as it is less irritating, while in Bright' s disease chloroform is generally 
more injurious than ether from the resultant albuminuria and tendency 
to fatty degeneration although ether is also believed by many to disturb 
the renal functions. Advanced diabetes contraindicates anaesthesia, 
the sugar increasing in the urine afterwards and coma and death some- 
times supervening in the course of a few days. Da Costa recommends 
that where there are symptoms of anaemia, an examination of the blood 
should be made before anaesthesia, and states that where the haemo- 
globin is found to be deficient, great care is necessary and that where 
it is lower than 50 per cent, of the normal, an anaesthetic is contra- 
indicated. 

Practical Anaesthesia. — The patient should have a light, easily di- 
gested meal 2-4 hours before, so that the stomach may be empty and 
vomiting avoided as far as possible. The bowels should also be regu- 
lated the day before for the same reason. He should then be laid on 
a table of suitable height with a low pillow, and should remove false 
teeth and any other foreign object from the mouth. The clothing 
about the neck, chest and abdomen is to be loosened or removed to 
allow of perfectly free respiration, but warm blankets or warm bottles 
should be applied as far as possible to prevent the fall of temperature 
if the operation is likely to be a long one. The eyes are closed in 
order to protect the conjunctiva from the irritating vapor. The 
anaesthetic is then applied on a towel or on a mask, which ought to 
be freely permeable by the air, and ought not to fit closely to the face. 
It must be remembered that the air passes through cloth with much 
greater difficulty when it is wet by the saliva and mucus, and that a 
mask which is freely permeable at the commencement of an operation, 
may lead to asphyxia after it has been soaked during the first and 
second stages. The patient is instructed to breathe as regularly as 
possible, or to count from one upwards, and some of the anaesthetic is 
dropped on the mask. If the breath be held, the mask should be 
raised a little from the face, as the next inspiration will be a very deep 
one. During the excitement stage the respiration is irregular, and 
great care must be taken to avoid the inhalation of too concentrated 
vapor. As soon as the conjunctival reflex disappears, the mask is re- 
moved, and is replaced only when it reappears or when the patient 
evinces signs of pain. Throughout the anaesthesia, care must be taken 
to prevent any interference with the respiration by the operator lean- 
ing on the thorax or abdomen. Very often stertorous respiration sets 
in from the tongue falling back into the throat, and this has to be 
remedied by pressing forward the angle of the jaw, or if this is not 
sufficient, by pulling out the tongue with a blunt-pointed forceps. 
Vomiting is a very common occurrence in anaesthesia, and when it sets 
in, the head is turned to one side and the vomited matter removed 
with a sponge. 

A more serious accident is the failure of the respiration. A reflex 
arrest often occurs in the first stage, but is not of importance in itself, 



ETHER AXD CHLOROFORM. 175 

but only from the deep gasping inspiration which follows it. If the 
anaesthetic be given too long in concentrated form, however, the res- 
piration fails from direct action on the centre, and this demands im- 
mediate attention. The head ought to be lowered at once, and the 
lower limbs elevated, in order to drive the blood to the head as far as 
possible and thus remedy the anaemia of the brain from the weakness of 
the heart that accompanies the cessation of the respiration. The epi- 
glottis must be raised by pressing forward the angles of the jaw (Hare), 
or by dragging forward the base of the tongue with hook or finger. 
Artificial respiration in one or other form ought to be commenced at 
once, and carried on as long as is necessary ; a large number of methods 
of performing artificial respiration have been proposed, but they can 
only be taught in a practical class and need not be entered upon here. 
If the pulse is weak, intermittent pressure over the heart may aid it in 
carrying on the circulation, and it has been proposed to pass one hand 
up under the ribs, and then press the heart between the two hands and 
aid it in expelling its contents. If the heart stops at this stage, there 
is little hope of reviving the patient, although this can often be 
done in animals by kneading the heart between the two hands. Various 
drugs have been recommended in these cases, but it is exceedingly 
questionable whether they are really of service ; alcohol, ammonia and 
ether have been injected subcutaneously, and may conceivably cause such 
local irritation as to reinstate the respiration reflexly, although this is 
improbable. Strychnine, caffeine and atropine have been injected as res- 
piratory stimulants, and digitalis to strengthen the heart contraction ; as 
a matter of fact, however, if the circulation is strong enough to cause the 
absorption of these drugs and carry them to the respiratory centre and 
the heart, the patient will recover with the artificial respiration alone, 
while on the other hand, they are of no value unless absorbed. Xitrite 
of amyl is often given by inhalation in cases of accident, but the blood- 
pressure is so low already that there really seems no advantage in re- 
ducing it further, and amvl nitrite can have no other action. On the 
whole, it seems more than questionable whether drugs should be used 
at all in accidents during anaesthesia. 

In the course of very long operations it is recommended to allow 
the patient to almost recover consciousness at intervals, but this is often 
impossible without interfering with the course of the operation. It 
must be remembered that in prolonged anaesthesia comparatively small 
quantities are required to maintain unconsciousness when it is once 
completely reached, and at the same time that, owing to the fall of tem- 
perature and the prolonged action of the drug, the quantity necessary 
to produce cessation of the respiration and the heart is much smaller 
than during shorter operations. In order to induce anaesthesia within 
a reasonable time, comparatively strong vapor may be used at first, 
but as soon as unconsciousness is reached, the vapor ought to be diluted 
as far as is compatible with the continuation of the narcosis. 

On the completion of the operation, the patient seldom requires fur- 
ther attention from the anaesthetist ; after prolonged anaesthesia heat 



176 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

may be applied by warm bottles, etc., as the temperature often continues 
to fall for some time after the administration of the drug has ceased. If 
vomiting persists after the recovery of consciousness, ice may be sucked, 
or bismuth may be prescribed. The inhalation of vinegar has been 
recommended and relief is sometimes given by lavage of the stomach. 

The patient should always be placed in the recumbent position when 
possible, as otherwise the weakened heart tends to drive the blood in the 
direction of least resistance, that is, downwards, and in the depressed 
condition of the vaso-motor centre, this is not counteracted by the con- 
traction of the arterioles of the abdomen, and anaemia of the brain and 
syncope are liable to result. The operation ought not to be commenced 
until anaesthesia is complete ; otherwise shock may result and, in the 
weakened state of the central nervous system, may lead to fatal results. 

Various drugs have been advised as preliminaries to anaesthesia, 
generally with the object of preventing the reflex arrest of the respira- 
tion and heart. Thus atropine and sparteine have been proposed to 
paralyze the vagus, and to arrest the mucous secretion and vomiting, 
and spraying of the nose with cocaine has recently been advised to par- 
alyze the sensory terminations and so prevent the irritation which sets 
up the reflexes. As a matter of fact, however, the reflex arrest of the 
respiration and the slowing of the heart may rather be regarded as 
monitions that the vapor is too concentrated than as dangers in them- 
selves. It has been proposed to dilute ether or chloroform vapor with 
oxygen instead of air, but there seems no theoretical reason why this 
should have any advantages, and in practice it has been used in too 
limited a number of cases to allow of trustworthy inferences. 

Of late years a good deal of interest has been excited by the dis- 
covery that the perils of anaesthesia are not over when consciousness 
returns, but that fatal consequences may follow several days later. 
These late fatalities are due to fatty degeneration of the heart and 
kidneys or to diabetic coma in the case of chloroform, to bronchitis, 
pulmonary oedema and pneumonia after ether. JNo reliable data are 
as yet available as to the frequency of these sequelae, as it is very diffi- 
cult to distinguish between the results of the anaesthetic and the ordi- 
nary forms of disease. Even the proportion of cases in which albumi- 
nuria occurs after chloroform seems to vary remarkably in different 
hospitals, for it is given as low as 5 per cent, by some authors and as 
high as 30 per cent, by others ; this may perhaps be explained by differ- 
ences in the duration of the anaesthesia. The irritant effects of ether and 
the liability of pulmonary affections afterwards have been so evident that 
some surgeons have returned to the use of chloroform, believing that 
the late effects in ether claimed as high a proportion of victims as the 
more immediate effects of chloroform. Dreser has shown, however, 
that the irritant action of ether and its consequent dangers may be 
largely avoided by the use of dilute vapor. Some anaesthetists have 
found albumin and casts in the urine in a considerable proportion of 
cases in which anaesthesia had been induced by ether, but others have 
failed to detect any action on the kidneys after this anaesthetic. 



ETHER AND CHLOROFORM. 177 

Therapeutic Uses. — Anaesthesia is generally induced for the purpose 
of surgical operations and examinations, and in labor. Until recent 
years, when it was necessary to perform an operation or manipulation 
involving much pain, the surgeon had to consider only which of the 
two general anaesthetics was the better adapted to the case. But the 
improvements introduced in the methods of inducing local anaesthesia 
and the reintroduction of nitrous oxide as a surgical anaesthetic have 
now enlarged his field of choice, and the further question has to be met 
whether unconsciousness is desirable, or whether the necessities of the 
case may not be met by paralyzing sensation at the seat of operation 
only. The advantages claimed for local anaesthesia will be discussed 
under cocaine, but the general conditions in which chloroform and 
ether are to be preferred may be stated shortly (see also nitrous oxide). 
General anaesthesia is absolutely essential where complete relaxation of 
the muscles is desired, and where the movements of the patient may 
imperil the success of the operation. Operations on the abdominal 
organs and around joints and such others as involve wide and deep 
incisions will almost certainly continue to be performed under chloro- 
form or ether, although a few such operations have been attempted 
under cocaine. In many less serious operations it is necessary also to 
have recourse to the older methods, which allow greater freedom to the 
surgeon, who is under no apprehension that he may reach a sensitive 
area and has thus one less source of anxiety than if the anaesthesia were 
localized. Another argument for the use of general anaesthetics is the 
effect which the anxiety and the sights and sounds of the operating 
room may have on a nervous patient even when no actual pain is felt. 
And a considerable amount of practice is required before complete local 
anaesthesia can be induced over an extensive field of operation, while 
the surgeon has often to interrupt his manipulations in order to admit 
of a fresh area being rendered analgesic. But there is no question that 
many operations in which ether or chloroform has hitherto been 
employed, will in the future be performed more often under local anaes- 
thesia or nitrous oxide. In this class may be included most minor 
operations in which only very short or partial anaesthesia is necessary 
and in which no complications are to be anticipated. 

During labor only the lighter degrees of anaesthesia are necessary, 
the object being to dull the pain without lessening to any marked 
extent the reflex irritability of the spinal cord, and accidents are 
extremely rare in this use of anaesthetics, although the common state- 
ment that they are unknown is incorrect. Some cases have been 
recorded in which it is believed that chloroform was fatal to the child 
and not to the mother, but it is, of course, impossible to state with cer- 
tainty that the anaesthetic was the cause of death. If too deep anaes- 
thesia is produced, however, it is quite conceivable that the labor 
may be prolonged, or the blood-pressure so reduced as to lead to 
an imperfect exchange of gases in the placenta and thus to the 
death of the infant ; or as another explanation it might be sug- 
gested that the irritability of the respiratory centre of the child may 
12 



178 ORGANIC DRUGS ACTING AFTER ABSORPTION 

be so reduced that it fails to react when the placental circulation is 
interrupted. 

Anaesthetics are also employed in cases of extreme irritability of the 
central nervous system, as in strychnine poisoning, tetanus or other con- 
vulsive affections. In order to reduce these, it is unnecessary to produce 
deep anaesthesia, a few whiffs of chloroform being generally sufficient 
to produce quiet, often without affecting the consciousness to any 
marked extent. In cases of very acute pain, chloroform or ether may 
be used, but as a general rule morphine or opium is preferable, as the 
action lasts much longer and the administration is much more con- 
venient. 

During the stage of excitement of anaesthesia, the dreams of the 
patient sometimes assume an erotic character, and charges of criminal 
assault have been repeatedly brought against surgeons by women whom 
they had anaesthetized. It is, therefore, advisable to give chloroform 
to women only in the presence of a third person. 

The local action of chloroform and ether on the stomach and skin 
is entirely independent of the action as anaesthetics, and has to be 
discussed separately (see page 181). 

Prepakatioxs. 

U. S. P. — Chloroform um, a liquid containing 99-99.4% by weight of 
absolute chloroform (CHC1 3 ) and 0.6-1% of alcohol. 

iETHER, ether, a liquid composed of about 96 fo by weight of absolute 
ether or ethyl oxide ((C 2 H 5 ) 2 0) and about 4% of alcohol containing a little 
water. 

B. P. — Chloroformum, chloroform (CHC1 3 ), must have a specific gravity 
of 1.490-1.495, that is, must contain 99 per cent, of absolute chloroform. 

JEther, ether, or sulphuric ether, a volatile liquid prepared from alcohol 
and containing not less than 92 f by volume of pure ether or ethvl oxide 
((C 2 H 5 ) 2 0). 

JEther Purificatus, ether freed from most of the alcohol or water, and 
of 0.720-0.722 specific gravity. 

Chloroform is ordinarily formed by the action of chlorine on alcohol, the 
chlorine being added in the form of chlorinated lime. The crude drug is 
purified by repeated washing with water and sulphuric acid, and dried over 
calcium chloride. The fatalities following its use have frequently been 
ascribed to impurities, and a certain demand has arisen for a purer article 
than that required by the pharmacopoeias. Another method of preparation 
has therefore been introduced, the decomposition of chloral by soda (Chloro- 
formum e Chloral prseparatum). Other pure forms are prepared from ordi- 
nary chloroform by crystallizing it by cold (Pictet), or by forming a com- 
pound with salicylid and decomposing it again by slight heat, Chloroform 
(Anschutz) or Chloroform (Salicylid). 

The impurities of chloroform are due partly to imperfect manufacture and 
partly to decomposition. Along with the chloroform there distils over a 
small quantity of heavy oily fluid, which may be isolated by Pictet' s method, 
but whose composition is entirely unknown. DuBois-Keymond found that 
this fluid acted more strongly on the heart than pure chloroform, but it is 
very questionable whether the minute quantities inhaled in ordinary anaes- 
thesia produce effects of any importance, and, on the other hand, it is quite 
certain that the use of absolutely pure chloroform does not prevent accidents. 
Chloroform undergoes decomposition when exposed to light and air, hydro- 



ETHER AND CHLOROFORM. 179 

chloric acid and chlorine being set free in small quantity. These can affect 
the course of anaesthesia only through their local irritant action, but if pres- 
ent in sufficient quantity may cause the respiration to be more irregular than 
usual in the earlier stages ; the chloroform used for anaesthetic purposes 
ought, therefore, to be kept in a dark place or in colored bottles. Another 
decomposition occurs when chloroform is evaporated in the neighborhood of 
a large flame, such as from gas or lamps, and hydrochloric acid and phosgen 
(CC1 2 0) are formed, the latter being a gas with exceedingly irritant prop- 
erties. 

Chloroform is a heavy volatile fluid, of characteristic pleasant odor and hot 
sweetish taste. Its specific gravity is 1.490 (U. S. P.) and 1.490-1.495 (B. P.), 
and it boils at 60-62° C. A number of tests are given for impurities, but 
those of importance can generally be detected by the odor, especially if 
some chloroform be allowed to evaporate in a watch-glass, when the last 
drop ought to have no irritant effect when inhaled. Chlorine and hydro- 
chloric acid may be tested for by shaking the chloroform with distilled water, 
and testing the latter with potassium iodide and starch and with silver ni- 
trate. The water ought to give no acid reaction to litmus. If left in contact 
with concentrated sulphuric acid, chloroform should not become darker within 
one hour, as this indicates the presence of some foreign unstable body. 
The other impurities require complicated chemical processes for their detec- 
tion. 

Ether is prepared by the action of sulphuric acid on alcohol, and is subse- 
quently purified by washing with water and alkalies. It seldom contains 
impurities of importance. Bruns supposed that the irritant, suffocating ac- 
tion of ether was due to its containing impurities, such as ozone, but it would 
lather seem due to the inhalation of concentrated vapor. iEther (B. P. ) is un- 
suited for anaesthesia, and, in fact, is entirely superfluous. iEther purificatus 
(B. P.) and iEther (U. S. P.) are practically identical and are the forms in- 
tended for inhalation. Ether is a very volatile fluid, of a suffocating, irri- 
tant odor and bitter taste. Its specific gravity is .725-. 728 U. S. P., and 
.720-722 B. P., and its boiling point is 36-37° C. It evaporates very rapidly 
in the air and should leave no foreign odor and no residue. It should not 
color litmus paper, nor be colored within an hour when shaken with potas- 
sium hydrate solution. Ether vapor is exceedingly inflammable when 
mixed with air, and it should therefore be kept in a cool place, away from 
gas flames or lamps. 

Various other members of the fatty series have been introduced as o-eneral 
anaesthetics at different times, but none of them have proved to have any 
advantage over chloroform and ether, and it is, therefore, unnecessary to 
enter into details regarding them. Fatalities have occurred after all of those 
that have received a wide trial. Among others, methylene bichloride, 
ethylene chloride, and ethylidene chloride have received extensive trial, but 

have fallen into disuse. Pental, trimethylethylene ((CH ) C CHCH.V has 

been introduced for short operations within the last few years, and possesses 
the advantage that no after-effects are suffered from, the" patient feeling per- 
fectly well a few minutes after regaining consciousness. Its use is not 
absolutely safe, however, as was once asserted, for several accidents have 
occurred under it within a comparatively short time. Pental produces 
anaesthesia before the reflexes disappear or the muscles relax, and not 
infrequently the jaws are tightly closed after consciousness is lost. In 
some cases tremor and convulsive attacks have occurred during its adminis- 
tration, but it seems to have very little action on the heart or circulation. 
In the frog it is said to paralyze the terminations of the motor nerves. 
Ethyl Bromide (C 2 H.Br) has also been used largely in recent years for short 
operations instead of chloroform, and produces anaesthesia with great rapid- 
ity. Consciousness returns more quickly after the removal of the mask than 
under any other anaesthetic, but on the other hand, die inhalation is not so 



180 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

pleasant as that of pental and patients complain of greater depression and 
discomfort afterwards. Hennicke found that 10 vol. per cent, of ethyl bro- 
mide were necessary to anaesthetize animals within 5 minutes, and that if 
this concentration were maintained, death occurred in 15 minutes, so that it 
is by no means to be considered a perfectly safe anaesthetic ; several deaths 
have occurred from its use in dentistry. Both pental and ethyl bromide are 
administered on a mask in the same way as ether. Ethyl bromide must be 
distinguished from ethylene bromide (C 2 H 4 Br 2 ) which is a much more dan- 
gerous anaesthetic. Ethyl bromide is very liable to decomposition when 
kept long, and is often furnished in an impure form ; it ought to be perfectly 
colorless, as a yellowish color indicates decomposition, often with the pres 
ence of free bromide. Methyl bromide (C*H 3 Br).is quite unsuitable as an 
anaesthetic as after the drug is withdrawn, the unconsciousness remains and 
may even become deeper ; this is perhaps due to the molecule being decom- 
posed and bromides being formed in large amounts. 

The other members of this series possess no practical importance. It may 
be mentioned that tetrachloride of carbon (CC1 4 ) differs from the others in 
causing convulsions, while perchlorethane (C 2 C1 6 ) is a crystalline solid and 
possesses too high a boiling point to be available for inhalation. Bromoform 
(CHBi'j) has anaesthetic properties resembling those of chloroform, but has 
never been largely used in medicine. Of late years it has been given 
internally in whooping-cough, and in this relation it is important to re- 
member that when given repeatedly it causes fatty degeneration. A 
number of cases of alarming poisoning in children have been recorded 
from the use of bromoform, one gramme being sufficient to cause total un- 
consciousness. 

Various Mixtures of the Anaesthetics have been advised at different 
times. Of these the ACE mixture (alcohol 1, ether 2 and chloroform 3 parts 
by volume) is the best known. Its use has, however, been attended with 
numerous fatalities, as was only to be expected from a consideration of the 
volatility of the different ingredients. Ether, being the most volatile, is first 
inhaled, and then chloroform, and last of all the alcohol. The safe concen- 
tration of ether is, however, much greater than that of chloroform, and a vapor 
which may be perfectly safe as long as it consists of ether for the most part, 
may become exceedingly dangerous when it consists of chloroform. This 
method, therefore, increases the responsibility of the chloroformist by leav- 
ing him in complete ignorance as to the composition of the anaesthetic at 
any given time. 

A new series of mixtures, advocated recently by Schleich, consists of dif- 
ferent proportions of chloroform, ether, and petroleum ether, the more 
volatile part of petroleum (boiling at 60-65° C). His object is to have a 
fluid which boils as near the blood temperature (38.4°C.) as possible but it is 
unnecessary to enter into the theoretical principles on which he based his 
mixture as these have proved to be erroneous and such a fluid as he advises 
has no constant boiling point (Braun). He records very successful results in 
a small number of cases, and there is no reason why his mixture should not 
be as safe as the pure anaesthetics, provided it is given with such precautions 
as are always taken as long as a remedy is on its trial. It is not to be 
expected, however, that it will prove a "safe " anaesthetic for the inexperi- 
enced and untrained to use, or, in fact, that any such anaesthetic will ever 
be discovered. The anaesthesia is induced and maintained for the most part 
by the ether, which forms 70-80 per cent, of his mixture and the 17^-24 per 
cent, of chloroform merely accelerates and deepens its action. The petro- 
leum ether is quite superfluous, and the danger of the mixture lies in the 
fact that the vapor consists at one time of ether mainly, while later most of 
it may be chloroform. In favor of the mixture of the two anaesthetics it has 
been urged that very small quantities are required to induce unconsciousness, 
while on the other hand, the respiration is more unfavorably influenced than 
by either of them given alone (Honigmann). 



ETHER AND CHLOROFORM. 181 

Local Action and Uses. 

In addition to their use as anaesthetics, chloroform and ether are 
sometimes prescribed for the same purposes as the volatile oils. 
Chloroform has a hot, sweetish taste, while ether is bitter and suffocat- 
ing in the mouth ; a sensation of heat and often of pain in the stomach 
follows when they are swallowed, and chloroform may cause gastric 
irritation and catarrh when given undiluted. The movements of the 
stomach are accelerated, and Batelli states that a certain amount of 
shortening of the muscular fibres occurs. The whole effect is similar 
to that produced by the volatile oils, but absorption probably takes 
place more rapidly. On the skin, ether evaporates too rapidly to 
cause much irritation, but chloroform is occasionally used as a rube- 
facient in the form of a liniment. 

Preparations. 

The pure substances may be administered by the mouth, but more fre- 
quently other preparations are prescribed. 

Chloroform, 0.5—1 c.c. (8-15 rnins.). 

JEther, 0.5-1 c.c. (8-15 mins.). 

Spiritus JEtheris (U. S. P., B. P.), 1-5 c.c. (30-90 m.). 

Spiritus JEtheris Compositus (U. S. P., B. P.) (Hoffmann's Anodyne) 
contains a number of esters of ethyl and other substances known as 
" ethereal oil,' 1 together with ether and alcohol, 2—4 c.c. (£-1 fl. dr.). 

Spiritus Chloroformi (U. S. P., B. P.), 1-4 c.c. (20-60 min.) (5-20 m. 
for repeated doses, B. P.). 

Emulsum Chloroformi (U. S. P.), 15-30 c.c. (J-l fl. oz.). 

Aqua Chloroformi (U. S. P., B P.). 

Linimentum Chloroformi (IT. S. P., B. P.). 

Tinctura Chloroformi et Morphinse Composita (B. P.) contains one per cent, of 
morphine hydrochlorate, chloroform, prussic acid, cannabis indica, capsicum 
and oil of peppermint, and represents the patented medicine " chlorodyne. ; ' 
Dose. 5-15 m. It is used as a soporific (see morphine). 

Ailther Aceticus (IT. S. P., B. P.), acetic ether, an ethereal fluid consisting 
of ethyl acetate, 1-3 c.c. (20-40 mins.). 

Therapeutic Uses. — These preparations are used for the same pur- 
poses as the corresponding preparations of the volatile oils. Thus the 
spirits and emulsion may be prescribed as carminatives or in colic, 
while the liniment is used as a counter-irritant. Chloroform water is 
an antiseptic of considerable power, but is too volatile for surgical use. 

Spirits of ether and ether itself are often given internally or sul>- 
cutaneously in cases of shock or sudden collapse in the same way as 
brandy or whiskey, though Elfstrand states that ether injected hypo- 
dermically has no effect on the heart or blood-pressure ; spirits of 
ether contains a much larger percentage of alcohol than ordinary 
whiskey. Both ether and chloroform, but more especially the latter, 
have been used internally for tapeworm with success. There is always 
some danger, however, that, besides destroying the parasite, they may 
cause irritation and lasting injury to the intestinal wall. 

Hofmann's anodyne is a favorite carminative, and is often added to 
other drags to lend them an agreeable odor and taste. It is also used 



182 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

in dilution as a stimulant in the same indefinite way as wine and 
spirits, and its large percentage of alcohol, together with the bouquet 
given it by the various esters present, entitle it to be ranked among 
the alcoholic preparations. 

Both spirits of ether are used occasionally in expectorant mixtures 
and are believed to increase the bronchial secretion. 

Ether evaporates very rapidly and leaves a sensation of cold, and 
when thrown on the skin in a fine spray it produces sufficient cold 
to numb sensation in the part and allow of minor surgical operations. 
(See uses of cocaine.) Instead of ether still more volatile substances, 
such as ethyl chloride (boiling point 12.5° C.) and methyl chloride 
(boiling point — 23° C.) have been introduced. The latter is supplied 
in pressure cylinders, and is allowed to escape against the skin, while 
the others are thrown against it by pumping air through them. The 
local anaesthesia produced bears no relation to their action when 
inhaled, but is due simply to the cold produced by their evapora- 
tion. The vessels of the part contract, and the absence of blood and 
hardness of the tissues facilitate some operations, but the subsequent 
reaction is liable to produce considerable soakage of blood from the 
wound. The cold elicited ought not to be great enough to actually 
freeze the tissues, otherwise the healing may be slow. The intense 
cold is often quite as painful as the operation itself would be without 
any anaesthetic. 

Bibliography of Chloroform and Ether. 

The literature up to 1880 is given in Kappeler's " Anaesthetica," Stuttgart, 1880. 

Snow. On chloroform and other anaesthetics, London, 1858. 

Report of the London Chloroform Committee, Medico-chirurgical Transact., xlvii., 
1864. 

Sansom. Chloroform ; its action and administration, London, 1865. 

Claude Bernard. Lepons sur les ansesthesiques, Paris, 1875. 

Bernstein. Moleschott's Untersuch., x.,p. 280. 

Scheinesson. Arch. d. Heilkunde, 1869, p. 36. 

Knoll. Sitzungsber. d. Wiener Akad., lxxiv., 3 Abt., p. 233 ; lxxviii., 3 Abt., p. 223. 

Bowditch and Minot. Boston Med. and Surg. Journ., 1874, p. 493. 

Commission de la Soc. Med. d 1 emulation. Union Med., 1855. 

P. Bert. Comptes rend, de l'Acad., xciii., p. 768; xcvi., p. 1831. 

Dastre. Les Ansesthesiques, Paris, 1890. 

In regard to the recent controversy as to the cause of death in chloroform anaesthesia, 
consult Report of the Hyderabad Chloroform Commission, Bombay, 1891, and Lancet, 1890. 
The criticisms on the report are also dealt with in the Lancet, 1890-91, and in the 
British Medical Journal, 1890-91. 

Mac William. Proc. Roy. Soc, liii., p. 464. Journ. of Physiol., xxv., p. 235. 

Wood and Hare. Medical News, lvi., p. 190. 

Ciishny. Ztschr. f. Biol., xxviii., p. 365. 

Gaskell and Shore. Brit. Med. Journ., 1893. 

Hill. Brit. Med. Journ., 1897, April. 

Hieballa. Arch. f. exp. Path. u. Pharm., xxxiv., p. 137. 

Hogyes. Ibid., xvi., p. 81. 

Pohl. Ibid., xxviii., p. 239. 

Limbourg. Ibid., xxx., p. 93. 

Nauiverck. Deutsche med. Woch., 1895, p. 121. 

Poppert. Ibid., 1894, p. 719. 

Miculicz. Berlin, klin. Woch., 1894, p. 1035. 

Bruns. Ibid., p. 1147. 

Salkowski. Zts. f. klin. Med. (Suppl.), xvii., p. 77. 



NITROUS OXIDE. 183 

Bubs. Inaug. Diss., Berlin, 1893. 
Ungar. Vierteljahr. f. ger. Med., xlvii., p. 98. 
Strassmann. Virchow's Arch., cxv., p. 1. 
Ostertag. Ibid., cxviii., p. 250. 
Frankel. Ibid., cxxvii., p. 381 ; cxxix., p. 254. 
Mertens. Arch, de Pharmacodynam., ii., p. 127. 
Kastu. Mester. Zts. f . klin. Med., xviii., p. 469. 
Taniguti. Virchow's Arch., cxx., p. 121. 
Budenko. Ibid., cxxv., p. 102. 
Savelieff. Ibid., cxxxvi., p. 195. 
Ambrosias. Ibid., cxxxviii., Suppl., p. 193. 
Kast. Zts. f. phys. Chem., xi., p. 277, and xii., p. 267. 
Lippmann. Mittheil. a. d. Grenzgebiet der Med. u. Chir., iv., p. 21. 
Selbach. Arch. f. exp. Path. u. Pharm., xxxiv., p. 1. 
Becker. Virchow's Arch., cxl., p. 1. 
Spenzer. Arch. f. exp. Path. u. Pharm., xxxiii., p. 407. 
Bosenfeld. Ibid., xxxvii., p. 52. 

Dreser. Beitriige zur klin. Chirurg., x., p. 412, and xii., p. 353. Arch. f*. exp. 
Path. u. Pharm., xxxvii., p. 375. Bulletin of Johns Hopkins Hospital, vi., p. 7, 1895. 
Hennicke. Inaug. Diss. Bonn., 1895. 
Heymanns et Debuck. Arch, de Pharmacodyn., i., p. 1. 
B. du Bois-Beymond. Therap. Monatsch., 1892, p. 21. 
Baton. Phil. Trans. Roy. Soc, 1894, p. 251. 
Lambert et Gamier. Jour, de Phys., ii., p. 902. 
Pereles u. Sachs. Pfliiger's Arch., lii., p. 526. 
Waller. Brain, xix. , p. 43. 

Poroschin. Centralbl. f. d. med. Wiss., 1898, p. 305. 
Kemp. New York Med. Journ., 1899, ii., p. 732. 
Thompson, Buxton, Levy. Brit. Med. Journ., 1900, ii., p. 833. 
Duplay et Hallion. Arch. gen. de Med., clxxxvi., p. 129. 

Da Costa. American Medicine, 1901, May 18th. Annals of Surgery, 1901, Sept. 
Brawn. Arch. f. klin. Chirurg., lxiv., p. 201. 
Honigmann. Arch. f. klin. Chirurg, lviii., p. 730. 
Kionka. Ibid., 1., p. 339. 

Bick. Arch. f. exp. Path. u. Pharm., xlii., p. 412. 
Elfstrand. Ibid., xliii., p. 435. 

Sackur. Virchow's Arch., cxxxiii., p. 30. (Pental. ) 
Hollander. Therap. Monatsheft, 1891, p. 509 ; 1892, p. 19. 
Friedldnder. Ibid., 1893, p. 42. 
Bauchwitz. Ibid., 1893, p. 352. 
Bieth. Ibid., 1893, p. 427. 
Beinecke. Ibid., 1898, p. 404. (Bromoform.) 

3. Nitrous Oxide. 

The oldest of the anaesthetics, nitrous oxide, N 2 0, does not belong 
to the methane series, but may be discussed at this point. 

Symptoms. — When a mixture of nitrous oxide and air is inhaled 
for a few seconds, a condition resembling alcoholic intoxication is 
produced, with much hilarity and laughter, so that the oxide is 
known popularly as " laughing gas." Even at this point a certain 
amount of anaesthesia is obtained, and it was the observation that persons 
falling during this stage did not complain of pain that first suggested to 
Wells the anaesthetic properties of the gas. Davy had noted these 
forty years previously, but his suggestion that nitrous oxide might be 
used in surgical operations passed unnoticed. 

The inhalation of a mixture of nitrous oxide, 4 parts, and oxygen, 
1 part, causes after a few seconds a rushing, drumming, hammer- 
ing in the ears, indistinct sight, and a feeling of warmth and com- 
fort. The movements become exaggerated and uncertain, the gait is 



184 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

staggering, and the body sways from side to side. The patient seems 
brighter and more lively, and often bursts into laughter. Somewhat 
later a feeling of drowsiness may come on, but this is not constant ; 
the sensibility to pain is much less acute than normally, but no com- 
plete anaesthesia is produced by this mixture of gases ; the sense of 
touch is comparatively little altered, and total unconsciousness never 
results. The pupil is generally slightly dilated, the face flushed, and 
the pulse somewhat accelerated. 

When pure nitrous oxide is inhaled without the admixture of oxy- 
gen, the patient passes almost instantaneously through the symptoms 
already described, but then loses consciousness completely ; the face is 
cyanotic, the respiration becomes stertorous and dyspnoeic and ceases 
after a weak convulsion, while the heart continues to beat for some 
time afterwards. If the mask through which the patient has been 
inhaling the gas be removed when the cyanosis becomes marked, very 
complete anaesthesia lasts for 30-60 seconds, and the patient then 
recovers within a few minutes and suffers from no after-effects what- 
ever. No prolonged anaesthesia can be produced, however, as the res- 
piration becomes endangered if the mask be kept on longer than the 
beginning of the cyanotic stage. 

Action. — Nitrous oxide supports combustion outside the body, for if 
a glowing splinter of wood be held in it, it bursts into flame exactly 
as if it were immersed in oxygen. It was accordingly believed at one 
time that nitrous oxide supported the combustion of the living tissues 
in the same way as oxygen, but this has been disproved, for as far as 
the metabolism of protoplasm is concerned, nitrous oxide behaves in the 
same way as any other indifferent gas, such as hydrogen or nitrogen ; 
that is, the tissues exposed to it suffer from asphyxia owing to the oxygen 
of the air being excluded. Thus, plants do not grow in an atmosphere 
of nitrous oxide and seeds do not germinate. Animals die after in- 
haling nitrous oxide in almost the same time as after hydrogen or 
nitrogen, and at death the spectrum of the blood shows no oxyhemo- 
globin to be present, the tissues having used up all the available 
oxygen. Nitrous oxide, therefore, does not support combustion in the 
animal body, the nitrogen is not split off from the oxygen as it is when 
the oxide is exposed to high temperatures outside the body. 

Another question is whether nitrous oxide behaves only as an in- 
different gas in the body, or whether it has not some special effect on 
the central nervous system, although in the rest of the tissues it acts 
only by excluding the oxygen. The earlier workers in this field held 
that it affected the central nervous system only by cutting off its sup- 
ply of oxygen, but this has been shown to be erroneous, for nitrous 
oxide acts as a depressant to the central nervous system by virtue of its 
molecular form just as chloroform or ether does. This has been shown 
in a variety of ways ; thus, if it were a perfectly indifferent body no 
more effect would be produced by it when mixed with one fourth of its 
volume of oxygen than by air, which consists of 1 part of oxygen 
and 4 parts of an indifferent gas, nitrogen. But 80 per cent, nitrous 



NITROUS OXIDE. 185 

oxide has definite effects on the behavior of animals, as has been men- 
tioned, and even 73 per cent, produces some slowing of the respira- 
tion. The narcotic action was demonstrated very clearly by Paul Bert 
in a series of experiments on man and animals. He noted that only 
imperfect anaesthesia was produced by 80 per cent, nitrous oxide, while 
the pure gas produced asphyxia. The problem was to introduce as 
much gas into the blood as would pass in under pure nitrous oxide, 
and at the same time to supply sufficient oxygen to prevent asphyxia. 
The absorption of nitrous oxide depends upon its partial pressure in 
the lungs, as it is simply dissolved in the blood without forming any 
real combination with it, and the quantity absorbed by the blood may 
be augmented by increasing the barometric pressure. Bert, therefore, 
administered a mixture of 80 parts nitrous oxide and 20 parts oxygen 
to animals in a glass case in which the pressure was raised one fourth 
above the ordinary atmospheric pressure. The absorption of the 
nitrous oxide was the same as if the animal had breathed the pure gas 
at the ordinary air pressure, and at the same time as much oxygen was 
absorbed as in ordinary air. The result was a complete anaesthesia 
without asphyxia, which could be maintained for 3 days without in- 
jury to the animal (Martin). Kemp has recently shown that mix- 
tures of oxygen and nitrous oxide can be inhaled for some time and 
produce anaesthesia, which passes off at once when nitrogen is substi- 
tuted for nitrous oxide. He has further investigated the blood gases 
during nitrous oxide anaesthesia, and finds that the oxygen contained 
in the blood at the deepest stage of anaesthesia is quite sufficient to 
maintain life and consciousness were no nitrous oxide present. Again 
Goltstein found that frogs were narcotized in 5 J minutes in an atmos- 
phere of nitrous oxide, in 1J hours in hydrogen, and showed that the 
narcosis and death in mammals from nitrous oxide differed in several 
details from that under indifferent gases. There can, therefore, be no 
doubt that nitrous oxide has distinct effects on the central nervous 
system, although it is indifferent to the other tissues. A further ques- 
tion arises, whether the anaesthesia produced by it in ordinary use is 
due to this specific action on the nerve cells alone or to the asphyxia. 
Wood has shown that even a slight admixture of oxygen (3 per cent.) 
delays anaesthesia considerably, so that the lack of oxygen appears to 
aid the direct effects of the anaesthetic. Bert's and Martin's experi- 
ments would indicate that death occurs not from the direct action of the 
nitrous oxide on the respiratory centre, but from the lack of oxygen, al- 
though the depression of the centre is undoubtedly a contributing factor. 

The same question arises regarding the action on the nerve cells as 
has been met with in the members of the methane series, and here 
again the preliminary excitement would seem to indicate not stimu- 
lation of the brain areas, but lessened activity of the functions of 
control and restraint. 

The respiratory centre is depressed when the gas is inhaled in com- 
paratively dilute form, for Zuntz and Goltstein found the breathing 
slower and deeper after 73 per cent. The respiration ceases some- 



186 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

what earlier under nitrous oxide than under indifferent gases, which 
would indicate that the cessation of the breathing is due at any rate 
in part to the specific depressant action. In asphyxia from nitrous 
oxide there is less convulsive movement than under hydrogen, owing 
to the general depression of the nerve cells. 

The circulation is little affected by the nitrous oxide directly, the rise 
in the blood-pressure and slowness of the pulse being due to the 
asphyxial condition of the blood ; the pulse is not so slow as in ordinary 
asphyxia or in asphyxia from nitrogen or hydrogen, because the in- 
hibitory centre is less capable of activity. The heart is not affected 
directly, but only by the lack of oxygen. 

Nitrous oxide is dissolved in the blood exactly as in water. There 
is no combination formed with any of the constituents, nor is the 
haemoglobin altered in any respect. 

Nitrous oxide is a gas at ordinary temperature and pressure, and is 
invariably administered by inhalation from a cylinder into which it 
has been forced under high pressure. The mask generally covers both 
nose and mouth, and the inhalation is carried on until distinct cyano- 
sis appears, when the anaesthesia is sufficient to allow of short oper- 
ations, such as those of dentistry. It is much the safest of the anaes- 
thetics, for millions of persons have been subjected to its influence, 
and as yet only ten cases of death are reported from its use, and sev- 
eral of these do not seem to have been due to the direct action of the 
gas. Unfortunately, the anaesthesia cannot be kept up except for a 
very short time, which is quite insufficient to allow of ordinary oper- 
ative procedures. A number of attempts have been made to prolong 
the anaesthesia, of which Bert's was much the most successful. The 
operator, patient and attendants were enclosed in an air-tight chamber, 
the air pressure was raised by means of force pumps, and Bert's mixture 
of oxygen and nitrous oxide was inhaled by the patient. A whole series 
of major operations were performed in this way, the anaesthesia being 
complete as long as was desired, and the patient recovering a few 
minutes after the mask was removed. The only objections to the 
method were the great expense of the chamber and of pumping the 
air, and the inconvenience attending the whole procedure. Bert, there- 
fore, proposed later to induce anaesthesia by pure nitrous oxide, and 
then to substitute for it a mixture of oxygen and nitrous oxide, and to 
keep up the anaesthesia as long as desired by alternating between the 
pure gas and the mixture. A practical method of carrying out this 
form of anaesthesia has been devised by Hewitt, whose results have 
led to a wider trial of diluted nitrous oxide anaesthesia than it has 
hitherto had. His apparatus consists essentially of two reservoirs, the 
one containing oxygen, the other nitrous oxide, and of a mixing cham- 
ber with a stopcock by which the proportion of oxygen is regulated. 
A tube leads from the mixing chamber to the mask which must fit 
closely to the face. The inhalation is commenced with pure nitrous 
oxide or with a mixture containing only 2 per cent, of oxygen. When 
anaesthesia is attained the percentage of oxygen is increased to 5-8 per 



SOPORIFICS— CHLORAL. 187 

cent, by turning the stopcock, and the symptoms determine the further 
changes, returning consciousness necessitating a diminution in the 
oxygen, stertor and cyanosis an increase. This form of anaesthesia i< 
admirably adapted for minor operations and has been maintained in 
some cases for as long as an hour. The circulation and respiration 
are less seriously altered than by any other method that induces 
general anaesthesia, and the return of consciousness is almost immediate 
The great drawback to its use is the cumbrous apparatus required and 
the large amount of gas used, amounting to about 100 gallons for 
anaesthesia of half an hour. Complete muscular relaxation is seldom 
attained and this precludes its use in many operations, in which how- 
ever it may be employed at first and then be replaced by chloroform 
or ether, whose preliminary disagreeable effects are thus avoided. 
Klikowitsch proposed the use of 80 per cent, nitrous oxide, not for 
complete anaesthesia, but to relieve pain and spasm in cases of asthma, 
in labor and similar conditions. The patient could inhale it if neces- 
sary without the presence of a medical attendant, and it had the ad- 
vantage over the other depressants that it need only be inhaled when an 
attack of pain was approaching and that it left no depression afterwards. 

The high blood-pressure induced by nitrous oxide asphyxia is some- 
times said to be dangerous in elderly persons from their liability to 
apoplexy, and of the few fatalities under the gas several would seem 
due rather to this than to the drug directly, but the danger is often 
overstated, and, in fact, it is a question whether the shock caused by the 
operation without gas would not be more dangerous than the effects of 
the gas itself. No such symptoms arise when the nitrous oxide is 
diluted with oxygen as in Hewitt's method. 

Occasionally some glycosuria occurs after the inhalation, not owing 
to the gas itself, but to the accompanying asphyxia. It is merely tem- 
porary and has no practical importance. 

The treatment of accidents in anaesthesia under nitrous oxide con- 
sists in artificial respiration alone. 

Bibliography. 

Paul Bert. Comptes rendus, lxxxvii., p. 728, and xcvi., p. 1271. 

Hermann. Arch. f. Anat : und Phys., 1864, p. 521. 

Jolyet et Blanche. Arch, de Phys., 1873, p. 364. 

Goltstein. Pfliiger's Arch., xvii., p. 331. 

Klikowitach. Virchow's Arch., xciv., p. 148. (Literature.) 

Martin. Comptes rendus, cvi., p. 290. 

Van Arsdale. Am. Journ. Med. Sciences, cii., p. 131. 

Wood. Dental Cosmos, 1893. 

Kemp. Brit. Med. Journ., 1897, ii., p. 1480. 

Hewitt. Anaesthetics and their administration, London, 1900. 

4. Soporifics. — Chloral. 

Some twenty years after the introduction of the anaesthetics, a new 
interest was given to the methane series by the examination of the ac- 
tion of chloral by Liebreich. Henceforth the attention of' investigators 
was diverted from the quest of anaesthetics to that of hypnotics, with 



188 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

the result that a very large number of bodies have since been suggested 
for this purpose and that a few valuable drugs have been added to 
therapeutics. These soporifics, or narcotics, have the same general 
action as the anaesthetics, but are used only to produce the first effects 
of imperfect consciousness or sleep. The anaesthetics might be used 
for this purpose were it not for the comparatively short time during 
which their action persists. Narcotics are required to produce a slight 
but lasting effect, and for this purpose the gradual absorption from the 
stomach is better adapted than the rapid absorption and equally rapid 
elimination by the lungs. The narcotics are, therefore, less volatile 
than the anaesthetics, and ought to be soluble in water and not irritant 
in the stomach, so as to permit of rapid absorption. Chloral is still 
the best known and most widely used member of this group. 

Symptoms. — In small quantities chloral produces drowsiness and 
weariness, which soon pass into a condition resembling natural sleep 
very closely, from which the patient can be awakened by ordinary means, 
such as touching, loud sounds, or pain. The respiration and pulse 
are somewhat slower than in waking moments, but scarcely more so 
than in natural sleep, and the somewhat narrowed pupil and unaltered 
excitability of the reflexes are also common to both conditions. As a 
general rule, the sleep passes off in 5-8 hours and leaves no unpleasant 
results, but sometimes headache, giddiness and confusion are com- 
plained of. Occasionally no real sleep is produced by chloral, a 
condition exactly resembling alcoholic intoxication following its ad- 
ministration and continuing for some time. When larger quantities, 
e. g., 5 G. (75 grs.), are taken, the sleep is much deeper, the patient 
cannot be aroused to complete consciousness, the reflexes are distinctly 
lessened and the sensation of pain is less acute, although no complete 
anaesthesia is present. The respi rations are fewer and the pulse may 
be slow and somewhat weak. The sleep lasts very much longer (10- 
15 hours), and nausea, vomiting, headache and confusion often remain 
after consciousness is regained. In still larger quantities chloral pro- 
duces a condition resembling exactly the third stage of anaesthesia. 
The reflexes are entirely absent and no movement is elicited by pain- 
ful operations, the muscles are completely relaxed, the respiration and 
pulse are both slow and weak, and eventually asphyxia occurs from 
paralysis of the respiratory centre. The heart continues to beat for a 
short time after the breathing ceases. 

The first stage is the only one elicited in therapeutics. The use of 
chloral as an anaesthetic would be quite unjustifiable, because it is im- 
possible to adjust the dose accurately enough to allow of complete 
anaesthesia without danger of respiratory failure. 

Action. — The Central Nervous System is depressed and eventually 
completely paralyzed by chloral and its allies. Unlike the anaesthetics 
and alcohol, however, chloral rarely causes excitement, but this may 
be due to the facts that the surroundings of the patient are less likely 
to cause excitement and that the drug itself causes less local irritation. 
The results of psychological experiments on the effects of small doses 



SOPORIFICS— CHLORAL. ] 89 

of the narcotics seem to indicate that they all depress the sensory or re- 
ceptive functions of the brain, while its motor activity is much reduced 
by chloral and sulphonal, but may appear to be actually increased by 
paraldehyde ; this apparent stimulation is analogous to that under 
alcohol and may be explained by lessened control. The sleep induced 
by the dulling of the perceptions may be interrupted by more intense 
stimuli from without. In particular, acute pain may prevent sleep 
after chloral, which seems to have no specific effects on the algesic 
areas, such as is possessed by morphine ; the sensibility of the skin is 
also less affected by chloral than by morphine. In larger quantities, 
however, even very great disturbance of the environment produces no 
interruption of the sleep, and the reflex response to irritation is 
very much lowered. The motor areas of the brain cortex are rendered 
less irritable by chloral, and eventually fail to react to the strongest 
electrical stimulation. The reflexes of the spinal cord are depressed 
and finally paralyzed before the failure of the respiration. 1 The 
depression of the reflexes is one of the points which serve to differenti- 
ate the action of most of the methane series from that of the alkaloidal 
narcotics, such as morphine. The last part of the central nervous sys- 
tem to be attacked is the medulla oblongata, for although the respira- 
tion is somewhat slower and shallower after small quantities, it is 
scarcely more affected than in ordinary sleep, and Loewy found that 
both the excitability of the centre and the volume of the inspired air 
were very similar in the two conditions. As the dose is increased, 
however, the respiration becomes very slow and weak, and finallv 
ceases from paralysis of the centre. 

The heart is somewhat slower after chloral in moderate doses, but 
scarcely more so than in natural sleep. There is often some flushing- 
of the face and head from some obscure central action, but the blood- 
pressure is little affected except by large quantities, which reduce it 
considerably and at the same time cause marked slowness of the pulse. 2 
The depression of the blood- pressure is caused in part by paresis of the 
vaso-motor centre, in part by the effects on the cardiac muscle, and 
possibly in part by a direct action on the muscular walls of the vessels. 
It is much more evident in poisoning with chloral than with the other 
soporifics, this group presenting the same differences in this respect as 
the general anaesthetics. In both cases it is' to be noted that the mole- 
cule containing chlorine has the more powerful action on the circula- 
tion. In chloral poisoning, as in chloroform, the effect on the heart is 
so great as to give rise to anxiety quite apart from the condition of the 
respiration, and in fact some cases of poisoning are said to have termi- 
nated with failure of the pulse before the respiration, though this is 
unlikely. The extreme weakness of the heart may, however, aid the 

i T\\e statement is made that the reflex irritability is at first increased in the frog, 
but this may be attributed rather to the remote effects of the local irritation than to the 
direct action on the cord. 

2 Some investigators have stated that small quantities of chloral increase the arterial 
tension at first, but this must be very transient, if present, at all. 



/ 



A 



190 ORGANIC DRUGS ACTING AFTER ABSORPTION 

direct action of the drug in its effects on the respiratory centre. The 
alterations in the heart are similar to those produced by chloroform, 
the auricular contractions becoming weak earlier than the ventricular, 
and some dilatation occurring in both chambers. 

Locally, chloral has an irritant action when applied in concentrated 
solution and this leads occasionally to nausea and vomiting when it is 
prescribed with insufficient fluid. This irritant action induces redness 
and even vesication when chloral is applied to the skin ; it is said to 
corrode when applied to unprotected surfaces, and certainly possesses 
antiseptic properties like chloroform. It is rapidly absorbed from the 
stomach and carried to the central nervous system where it is taken up 
by the cells until they contain more than the blood corpuscles or the 
cells of other organs such as the liver. Liebreich introduced chloral as 
a hypnotic in the belief that it was decomposed in the blood and chlor- 
oform liberated, but this has been shown to be erroneous, no chloroform 
being found in the blood or expired air after chloral, and the drug 
itself having been found in the urine in combination with glycuronic 
acid. Chloral has no action on muscle or nerve in the living animal, 
but when it is applied to the exposed nerve it first irritates and later 
paralyzes it, and injected directly into the artery of a muscle it causes 
immediate rigor. The temperature falls after the administration of 
chloral from the lessened muscular movement, and perhaps from the 
increased output of heat through the dilated skin vessels. 

The effects of chloral on the tissue-change have been recently inves- 
tigated and found to correspond very closely to those of chloroform. 
Thus fatty degeneration of various organs has been produced by the pro- 
longed administration of chloral and of chloralamide, and the increase 
in the nitrogen, phosphates and sulphur, especially of the unoxidized 
sulphur, in the urine points to augmented destruction of the proteids 
of the body, together with imperfect oxidation. The acidity of the 
urine is much increased by the presence of urochloralic acid (a com- 
bination of chloral and glycuronic acid). The excessive production of 
this acid in the tissues has been said to be the cause of the alterations 
in the metabolism, and as a matter of fact Kleine has found that the 
addition of alkaline carbonates to the food prevents these effects of 
chloral. Chloral was formerly supposed to lead to glycosuria, but this 
has been shown to be erroneous, the reducing substance in the urine 
being urochloralic acid, and not sugar. In addition to this effect on 
the tissues generally, less oxygen is absorbed and less carbonic acid 
excreted owing to the diminished muscular movement. 

Chloral is reduced in the tissues to trichlorethyl alcohol (CCl 3 CH 2 OH) 
which combines with glycuronic acid and is excreted in this form in the 
urine. Some escapes by the kidneys unchanged, however, and some 
is thrown into the stomach and this may account for the nausea and 
discomfort felt after awaking in some cases. 

The other hypnotics of this series, with the exception of chloralose, 
correspond exactly with chloral as far as their action on the central 
nervous system is concerned. The chief difference in their effects is 



SOPORIFICS— CHLORAL. 191 

seen in the circulation and metabolism, which are comparatively little 
affected by those which do not possess substituted chlorine atoms. 

Paraldehyde and Sulphonal do not affect the heart directly, although 
they may cause a slight acceleration of the pulse through their depres- 
sant action on the inhibitory centre. They lessen the metabolism through 
their action on the central nervous system, but produce no such marked 
alteration in the proteid decomposition as follows the administration of 
chloral. Paraldehyde resembles alcohol in its effects, though it is a 
much more powerful narcotic and rarely induces any symptoms of ex- 
citement. Very large quantities of sulphonal and paraldehyde have 
been taken without fatal results, and in fact without any more serious 
consequences than prolonged unconsciousness, so that they are much 
safer narcotics than chloral. Paraldehyde, however, has a most un- 
pleasant odor and a hot, burning taste, which renders its administra- 
tion somewhat difficult. In addition it is excreted in part by the 
lungs, though mainly in the urine, and the odor remains in the breath 
for some time after the patient awakens. The insolubility of sulphonal 
in water renders its absorption very slow and imperfect, and sleep is 
therefore late in following its administration, while, on the other hand, 
depression, drowsiness and lack of energy are often complained of the 
day after. 

The use of sulphonal, especially when prolonged, has led in some 
cases to a series of symptoms, the most characteristic of which is the 
appearance in the urine of a reddish-brown pigment, haematoporphyrin, 
an iron-free product of the decomposition of haemoglobin. This occurs 
most frequently in anaemic women, and is accompanied by constipation, 
pain in the stomach region and vomiting, weakness and ataxia, confusion 
and partial paralysis, and eventually by suppression of the urine or by 
collapse and death. 1 Haematoporphyrin occurs in traces in the urine of 
the rabbit normally and in much larger quantities after the animal has 
been treated with sulphonal (Neubauer). Its appearance in the human 
urine appears due to some obscure change in the blood, and not to de- 
rangement of the renal functions, although in one case the kidneys were 
found to be diseased, and in animals the prolonged administration of 
sulphonal often causes albumin and casts in the urine, while hemorrhages 
in the kidneys have been produced in them by the administration of only 
a few doses. The amount of haematoporphyrin in the urine is some- 
times very large ; in one case Tyson and Croftan found that the quantity 
passed in one day indicated the destruction of one seventeenth of the 
total haemoglobin of the body. Very large doses of sulphonal are said 
to produce convulsive movements in animals, while ordinary ones cause 
sleep and subsequent drowsiness. Sulphonal is decomposed in the body 
and is excreted largely as ethylsulphonic acid in the urine, in which 
traces of the unchanged substance have also been found. The decom- 
position is a slow process, however, for Kast found sulphonal in the 
blood many hours after its administration. The ethylsulphonic acid 

1 Occasionally the haematoporphyrin appears several days after a single dose of sul- 
phonal or its allies, sometimes after an interval of one or two weeks. 



192 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

seems to have no action whatever in itself, so that the narcosis is due 
to the unchanged molecule of sulphonal. 

Sulphonal seems to have some deleterious action on the heart when 
used for long periods, and is a much less certain hypnotic in cases of 
cardiac disease than in other conditions. In order to avoid the 
poisonous effects, which he regards as due to the accumulation of the 
drug in the alimentary canal and blood, Kast recommends that it he 
taken in small quantities, as far as possible in solution, and that the 
administration be stopped at intervals to allow of the complete elimi- 
nation of the sulphonal already in the system. 

Butylchloral, or Crotonchloral, was said by Liebreich to possess a specific 
analgesic or anaesthetic action on the nerves of the face and. head, but this 
has been shown to be incorrect by v. Mering, and, as its effects are identical 
with those of chloral in almost all respects, crotonchloral seems entirely 
superfluous. 

Chloralamide has been introduced into therapeutics in the hope that the 
stimulant action of the formamide, which is formed by its decomposition, 
would counteract the depression of the circulation caused by chloral alone. 
From blood-pressure experiments it would seem that chloralamide fulfills 
those expectations, and has little or no action on the circulation except in 
poisonous doses. It is said to be less irritant than chloral in the stomach, 
but to be somewhat slower and less certain in its effects. Chloral is formed 
by its decomposition in the body, and is excreted as urochloralic acid, and 
fatty degeneration has been observed after its prolonged administration. 
On the whole it would seem to possess the cerebral action of chloral, with- 
out producing its effects on the circulation. 

Amylene Hydrate, or dimethyletbylcarbinol, has been advised as a 
hypnotic, and is more closely allied to paraldehyde in its effects than 
to any of the others. It is twice or thrice as powerful a hypnotic as paral- 
dehyde, however, while it is only one half as strong as chloral. It is said to 
depress the heart more than paraldehyde, but less than chloral, and to pro- 
duce excitement and convulsions in the carnivora, but not in the herbivora. 
Even in man, it causes excitement more frequently than most other sopori- 
fics, and Harnack and Meyer state that it first stimulates and then depresses 
the respiratory centre as well as other parts of the central nervous system, 
and that it induces a very marked fall in the temperature. The cardiac and 
voluntary muscle is first increased in efficiency and then depressed. It has 
little or no effect on the general metabolism, and is excreted in the urine in 
combination with glycuronic acid in the rabbit, but seems to undergo com- 
plete combustion in the tissues of the dog and in man. It is less certain in 
its action than chloral but has not received so wide a trial as it would seem 
to merit. A combination of chloral and amylene hydrate has been intro- 
duced under the name of Dormiol, but offers no advantages over chloral. 

Trional and Tetronal are very similar to sulphonal in their chemical 
structure, and have practically identical results with it in therapeutics, 
although their action on animals is somewhat more powerful. In some cases 
of treatment with trional hsematoporphyrin has been found in the urine. 

Urethane would possess all the advantages of the others with none of 
their disadvantages were not its effect on man much weaker and less con- 
stant. In many cases it is an almost perfect hypnotic, easily taken in solu- 
tion, producing light sleep with no after-effects, but in others it seems to 
have little or no hypnotic effect. It is' oxidized in the body to urea. 
Hedonal appears to have a greater hypnotic effect than urethane, but also 
fails to induce sleep in a considerable proportion of cases. It is followed by 
no after-effects and is oxidized in the body in the same way as urethane. 



SOPORIFICS— CHLORAL. 193 

Hypnone has not received extensive trial, but would seem to be inconstant 
in its effects. 

Hypnal, a combination of antipyrine and chloral, has been suggested as a 
hypnotic in cases of neuralgia, but has not been used largely as yet, and 
seems of doubtful value. 

Chloralose acts much more like morphine than like chloral, depressing 
the psychical functions, while increasing the reflexes until convulsions re- 
sembling those of strychnine may be produced. The heart is comparatively 
little affected, and the respiration remains strong unless very large doses are 
given. In man it induces sleep, which is sometimes attended by distinctly 
exaggerated reflexes however, especially when large doses are given. Some 
of the other compounds of chloral with the sugar series seem to promise 
more satisfactory results. 

Bromal (CBr 3 COH) differs in several respects from chloral in its action. 
In animals its injection is followed by restlessness and excitement, and then 
by stupor, which is often accompanied by dyspnoea, and ends in failure of 
the respiration, or in convulsions. The pupil is much contracted, and pro- 
fuse salivation is observed. It acts on the heart like chloral but is much 
more poisonous, and is scarcely used in therapeutics. 

Chloretone resembles chloral in most respects, but is less liable to irritate 
the stomach and does not appear to depress the circulation to the same ex- 
tent. Very large doses have been swallowed without producing any untoward 
symptoms, but the hypnotic effect is obtained by the use of smaller doses 
than are necessary in the case of chloral. Like chloral, chloretone has some 
virtues as an antiseptic, and in addition it paralyzes the terminations of the 
sensory nerves when it is applied locally and has proved of value as a local 
anaesthetic. 

Tolerance is soon acquired for each of these drugs, and when it is 
developed for one, large doses of any of the others are required in 
order to produce sleep. Tolerance for alcohol also involves the use of 
larger quantities of the hypnotics, and in fact often leads to the com- 
plete failure of any except the most powerful. 

Not infrequently the hypnotics lead to skin eruptions, especially 
when used for some time. These assume various forms, the most com- 
mon being of the erythema order, but among others urticaria, purpura, 
papular eruptions and blisters occur. 

Habit. — Prolonged abuse of chloral leads to a condition somewhat 
resembling that seen in chronic alcoholism or morphinism, and marked 
by general depression and cachexia, with impairment of the mental 
powers, digestive disturbance and exanthemata. The sudden with- 
drawal of the drug in these cases has sometimes led to symptoms re- 
sembling those of delirium tremens, which are especially dangerous 
here owing to the fatty degeneration of the heart which may be present. 

A few cases of sulphonal habit have also been reported, but this 
drug has not been known long enough to permit of its extensive abuse 
as yet. 

Preparations. 

Chloral (U. S. P.), Chloral Hydras (B. P.) (CCl s CH(OH 
CCI3COH -f H 2 0), a crystalline solid, of a characteristic fruity odor, and 
hot, acrid taste, readily soluble in water, alcohol, ether and oils, is almost 
invariably prescribed in dilute solution in syrup. Its deliquescent properties 
13 



194 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

preclude its use in most of the solid preparations, and its irritant effects coo* 
traindicate hypodermic injection. Dose, 0.5-2 G. (10-30 grs.), which may 
be repeated if necessary, in one or two hours. 

Syrupus Chloral (B. P.), £-2 fl. drs. (one drachm contains 10 grains of 
chloral). 

Paraldehydum (U. S. P., B. P.) (C fi H 12 3 ), a colorless fluid of strong, 
characteristic odor and burning taste. It may be prescribed in brandy and 
water, or in water up to 10%, or in capsules. Dose, 1-4 c.c. (15-60 m.). 

Sulphonal (B. P.) ((CH 3 ) 2 C(S0 2 C 2 H 5 ) 2 ), a crystalline powder, without 
taste or odor. It may be prescribed in powder form to be taken one to two 
hours before retiring, but is soluble in hot water or milk, and when given in 
solution acts more rapidly and leaves no confusion afterwards. It is pre- 
scribed in doses of 1-2 G. (15-30 grs.). 

Butylchloral Hydras (B. P.), or Croton chloral (CH 3 CHC1CC1 2 CH(0H) 2 ), 
resembles chloral and is prescribed in the same way, but generally in smaller 
doses— 0.3-1 G. (5-15 grs.). 
Nonoflicial. 

Trional and Tetronal resemble sulphonal closely, and may be prescribed in 
the same doses and forms. 

Amyleni Hydras ((CH 3 ) 2 COHCH 2 CH 3 ), a colorless liquid of pungent taste, 
and of an odor somewhat resembling camphor. It may be prescribed in 
capsules, or up to 10 c /o in water flavored with liquorice extract. Dose, 3-5 
c.c. (40-80 m.). 

Urethranum (NH 2 COOC,tL), a crystalline solid prescribed in water. Dose, 
5G. 

Hedonal a crystalline powder with a taste resembling that of menthol, 
very slightly soluble in water. Dose, 2 G. (30 grs.) in powder or tablets. 

Chloralamidum (CCl 3 CH(OH)— NHCHO) a white crystalline powder with a 
very faintly bitter taste. Prescribed in powder, or in solution in water, or 
spirit. Dose, 1-3 G. (15-50 grs.). 

Chloralose (C 8 H U C1 3 6 ), colorless crystals of very bitter taste ; it may be 
prescribed in capsules. Dose, 0.15-0.3 G. (2-5 grs.). 

Chloretone (CCl,C(CH 3 ) 2 OH), colorless crystals with a strong camphorace- 
ous odor, slightly soluble in water, very soluble in alcohol ; it may be pre- 
scribed in aqueous solution (about 1 per cent.) or better in tablets. Dose, 
0.3-1 G. (5-15 grs.). 

Therapeutic Uses. — These drugs are chiefly used to produce rest and 
sleep in cases of insomnia and in almost every form of nervous ex- 
citement. Until the discovery of the therapeutic value of chloral, 
opium was used in most of these cases, and when sleeplessness is due 
to pain it is s*till preferable to the more modern remedies, which have 
comparatively slight influence on acute pain, except in very large doses. 
But in delirium, mania and convulsions of various kinds, their action 
on the nerve centres is preferable to that of opium, especially where 
these convulsions are of spinal origin or of a reflex nature ; thus, in 
strychnine poisoning and in tetanus, chloral is of great value, although 
in the former it may have to be reinforced by chloroform during the 
convulsions. In delirium from fever or from ursemic intoxication and 
similar causes, comparatively small doses often produce most satisfac- 
tory results, and in various spasmodic affections, such as cough, asthma, 
and choreic movements, it is exceedingly useful. Chloral has also been 
advised to lessen the pains of labor. 

Most of the soporifics have been used more or less extensively as 
hypnotics in simple insomnia and in insanity, but when the disturb- 



SOPORIFICS— CHLORAL. 195 

ance assumes a more violent character there is a disposition to return 
to the use of chloral, as at once the speediest and surest remedy of the 
whole group. When there is any reason to suspect fatty degeneration 
of the heart, however, paraldehyde or some other hypnotic which does 
not contain chlorine ought to be substituted for it. Chloral is often 
prescribed along with opium, and, when thus combined, smaller quan- 
tities of each drug are required than would be necessary if either were 
prescribed alone, and the sleep following is very deep and restful. It 
is also used very often to reinforce the action of the bromides. 

Other Narcotics which for some purposes may be substituted for the 
members of the chloral group are alcohol, opium and its alkaloids, 
bromides, hyoscine, hyoscyamine and cannabis indica. 

Chloral has been used externally as a counter-irritant and antiseptic, 
but is more expensive than many other equally efficacious remedies. 
Chloretone solution is an efficient local anaesthetic on wounded sur- 
faces, and has been recommended in cases of gastric irritation and 
vomiting, which it relieves by paralyzing the terminations of the sen- 
sory nerves in the mucous membrane of the stomach. 

In cases of acute Poisoning with chloral the treatment consists in 
the immediate evacuation of the stomach by the stomach tube. Emet- 
ics are of less value owing to the depression of the medullary centres. 
The patient ought to be kept warm and caffeine or strychnine may be 
given as a respiratory stimulant, while the complete failure of the 
breathing has to be met by artificial respiration. In acute poisoning 
with the other members of the series the same general treatment is to 
be applied, but the prognosis is much more favorable than after chloral ; 
in one case in which 100 G. of sulphonal were swallowed, the recov- 
ery was attributed by the attendant physician to copious enemata of 
water. In chronic poisoning with sulphonal, the withdrawal of the 
drug is generally all that is required. In the chloral habit, the with- 
drawal has to be gradual and it may be necessary to send the patient 
to a retreat. 

Bibliography. 
Chloral. 

Liebreich. Das Chloral, ein neues Hypnoticum, Berlin, 1868. 
Lewisson. Arch. f. Anat. u. Phys., 1870, p. 346. 
Rajeivski. Centralb. f. d. med. Wiss., 1870, p. 211. 
Ha mack u. Witkowski. Arch. f. exp. Path. u. Pharm., xi., p. 1. 
Heidcnhain. Pfliiger's Arch., iv., p. 557, and xxvi., p. 137. 

v. Merino. Arch. f. exp. Path. u. Pharm., iii., p. 185. Zts. f. phys. Chem., vi., p. 
480. 

Preisendorfer. Deutsch. Arch. f. klin. Med., xxv., p. 40. 

Loewy. Pfliiger's Arch., xlvii., p. 601. 

Taniguti. Virchow's Arch., cxx., p. 121. 

Peiser. Inaug. Diss., Halle, 1892. 

Remertz. Inaug. Diss., Halle, 1893. Fortschr. derMed., 1893, p. 265. 

Haniack u. Kleine. Ztsch. f. Biol., xxxvii., p. 417. 

Kraepehn. Beeinflussung psychischer Vorgiinge durch Arzneimittel., p. 209. 

Paraldehyde. 

CerveUo. Arch. f. exp. Path., xvi., p. 265. 
Albertoni. Arch. Ital. d. Biol., iii., p. 197. 
Friedldnder. Therap. Monats., 1893, p. 144. 



196 ORGANIC DRUGS ACTING AFTER ABSORPTION 

Su]j)honal. 

Kast. Berl. klin. Woch., 1888, p. 309. Arch. f. exp. Path. u. Pharm., xxxi., p. 69. 
Smith. Zts. f. phys. Cliem., xvii., p. 1. 
Friedlander. Therap. Monats., 1894, pp. 183 and 370. 
Kastu. Weiss. Berl. klin. Woch., 1890, p. 621. 
Vanderlinden u. Debuck. Arch, de Pharmacodyn., i., p. 431. 
Neubauer. Arch. f. exp. Path. u. Pharm., xliii., p. 450. 
Ilaencl. Kraepelin's Psychol. Arb., ii., p. 320. 
Tyson and Crofion. Philad. Med. Journ., 1902, p. 882. 

Amylene Hydrate, and other Soporifics. 

v. Mering. Therap. Monats., 1887, p. 249. 
Friedlander. Ibid., 1893, p. 370. 

Harnaclc u. Meyer. Ztsclir. f. klin. Med., xxiv., p. 374. 
Lahousse. Arch, de Pharmacodyn., L, p. 209. ( P>utylchloral. ) 
Friedlander. Therap. Monats., 1893, p. 523. (Chloralamide. ) 
Manchot. Virehow's Arch., cxxxvi., p. 368. 

Henriot u. Richet. Arch, de Pharmacodyn., iii., p. 191. (Chloralose. ) 
Schmiedeberg. Arch. f. exp. Path. u. Pharm., xx., p. 203. (Urethane and the 
group in general. ) 

Bradbury. Croonian Lectures, Brit. Med. Jour., 1899. 

Houghton and Aldrich. Journ. Am. Med. Ass., Sept. 23, 1899. (Chloretone. ) 

Impens. Arch, internat. de Pharmacodyn., viii., p. 77. (Chloretone.) 

II. STRYCHNINE — NUX VOMICA. 

Strychnine is the chief alkaloid occurring in several species of 
Strychnos, of which the best known are Strychnos nux-vomica and 
Strychnos Ignatia. It is found chiefly in the seeds, and is generally 
accompanied by the nearly related alkaloid Brucine. 

A large number of alkaloids have been found to resemble strychnine in 
their action, such as the Thebaine found in opium, the Gelsemine of Gelsemium 
sempervirens, and the Calabarine of the Calabar bean, while it is difficult to 
decide whether several others ought to be classed with morphine or with 
strychnine. 

Strychnine seems to be a quinoline derivative, although its exact consti- 
tution is unknown. Its formula is C 21 H 22 N 2 2 , w T hile that of brucine is 
C 23 H 2fi N 2 4 . They are both derivatives of a substance of the formula 
C 15 H lt N 2 2 , brucine differing from strychnine in having two methoxyl 
groups. It seems not unlikely that they are both nearly related to cura- 
rine, the alkaloid of curara, which is derived from some other species of the 
genus Strychnos. 

The alkaloids of the strychnine group have a powerful stimulant 
action on the central nervous system, especially on the spinal cord, 
throughout the vertebrate kingdom. 

Symptoms. — In ordinary therapeutic doses strychnine, like other 
bitter substances (page 55), improves the appetite and often leads to a 
distinct amelioration of the subjective symptoms, the patient feeling 
stronger and more hopeful. The pulse is generally slower and the 
artery feels less compressible. The special senses are rendered more 
acute by small quantities of strychnine, for differences can be recog- 
nized between shades of color which seem identical to the normal 
vision ; the field of vision is widened, and in certain conditions of 
amblyopia light is rendered much more distinct. In the same way 
the hearing seems to be more acute, and the sense of touch is much 
more delicate. Some cases have been noted in which disagreeable odors 



STRYCHNINE — NUX VOMICA. 



197 



were rendered pleasant by strychnine, but this would seem to be a rare 
idiosyncrasy. In cases of poisoning with strychnine, the first symp- 
tom is often a more acute perception of external objects by the sen-*-, 
especially by the sense of touch, but this is not generally observed by 
the patient, whose first complaint is of a feeling of stiffness in the mus- 
cles of the neck and face. This is soon followed by an increased 
reflex reaction, so that a slight touch causes a violent movement, and 
even a sound or a current of air is sufficient to cause a sudden start. 
The increased reflex irritability is generally accompanied by some rest- 
lessness, and animals sometimes seem to make attempts to escape from 
bright light. Some tremor or involuntary twitches may be observed in 
the limbs, and then a sudden convulsion occurs in which all the muscles 
of the body are involved, but in which the stronger extensor muscles 
generally prevail. In animals, the head is drawn back, the hind limbs 
extended, and the trunk forms an arch with its concavity backwards 
(opisthotonos) (Fig. 13). In man, the same convulsions are seen and 

Fig. 13. 




A rabbit during a strychnine convulsion. 

are accompanied by strong contraction of the face muscles, producing 
a hideous grin which has been called the risus sardonicus. The res- 
piratory muscles are involved in the general paroxysm and the blood 
rapidly becomes deoxygenated, as is shown by the blue cyanotic color 
of the lips and face in man. The muscles feel hard and firm at the 
commencement of the convulsion, but very soon a tremor may be made 
out, which becomes more distinct, and after a few intermittent contrac- 
tions the animal sinks back in a condition of prostration (Fig. 14). The 

Fig. 14. 




A rabbit when the strychnine spasm is passing off. The head is supported to prevent it fulling on 

the table. 



198 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

respiration generally returns, and becomes fairly regular for a short 
time. Immediately after a convulsion the reflex irritability may be 
low, but it soon regains its former exaggerated condition and a second 
convulsion occurs, exactly resembling the first. Mammals, as a gen- 
eral rule, succumb after two or three convulsions, the respiration 
failing to return after the spasm. In some cases, however, the con- 
vulsions become shorter and the intervals of quiescence longer, the 
respiration becomes weak, the reflex irritability gradually lessens 
and the animal dies from asphyxia. In frogs, where the breathing 
can be dispensed with for long periods, the alternation of convul- 
sions and periods of quiescence may continue for hours or days, but 
these are of the same general character as those described in mammals. 
After very large quantities no convulsions may occur, the animal dying 
almost immediately of asphyxia from paralysis of the central nervous 
system. 

Action. — The whole character of the intoxication points to an affection 
of the Central Nervous System, and it has been found that the symptoms 
are unaltered when the drug is prevented from reaching the peripheral 
nerves and muscles. The chief symptoms arise from the spinal cord, 
for the convulsions are at least as well marked in frogs and mam- 
mals in which the brain has been destroyed or severed below the 
medulla oblongata. At the same time the brain is also believed to be 
affected, though to a less degree. The intellect in man remains un- 
clouded until the end, except for the asphyxia produced by the stop- 
page of the respiration ; the patient is perfectly conscious of his 
condition, and suffers excruciating pain from the violent contractions of 
the muscles. It is said that the increased reflex may be inhibited to a 
certain extent by the will, but during the convulsions no strength of 
will can cope with the irritability of the spinal cord. 

The special senses are rendered more acute by small doses of strych- 
nine and this is apparently due to its effects on the central nervous 
system in the case of touch, taste and smell, but there is every reason 
to believe that the increase in the field of vision and the increased 
sensitiveness to slight differences in light are to be attributed to its 
acting on the cells of the retina and not to cerebral changes. For 
when strychnine salts are injected in the temple or applied to the con- 
junctiva, the sight of the corresponding eye is improved while the 
other remains unaffected (Filehne); if the strychnine acted centrally it 
could do so only by being carried to the brain by the blood, but this 
would affect each hemisphere equally. The affection of one eye only 
is explained by the strychnine diffusing through the lymph spaces, and 
this has been shown to occur in the case of various dyes which were 
applied in the same way and were then found in the retina. 

As regards the effects of strychnine on the motor areas of the brain 
some difference of opinion exists, although the majority of those who 
have investigated the subject hold that the irritability of the motor 
parts of the cortex is distinctly increased except during a con- 
vulsion. 



STRYCHNINE— N TJX VOMICA. 199 

The convulsions are, as has been stated, of spinal origin. It has 
been shown in addition that they are reflex, that provided no stimulus 
reaches the cord from without, no convulsion occurs. As has been 
already remarked, the convulsions are preceded by a stage of increased 
reflex, and in fact the first convulsion is often seen to follow a stimulus, 
such as a blow or a loud noise. Afterwards they may seem to occur 
without any such impulse, but this is merely because a very slight or 
even imperceptible stimulus is enough to induce them. For ex- 
ample, a slight contraction of a muscle may induce a convulsion, 
as is seen very frequently in the frog, where a very slight stimulus, 
in itself apparently too weak to cause a convulsion, is followed by 
an ordinary reflex contraction, and this leads to a spasm. The 
absence of convulsions when external stimuli are cut off may, how- 
ever, be demonstrated conclusively in various ways. Thus Pouls- 
son found that a frog dipped in cocaine solution underwent no con- 
vulsions after strychnine, the cocaine used being sufficient to paralyze 
the sensory terminations, but not to have any direct effect on the cord. 
Claude Bernard showed this even more conclusively by dividing all 
the posterior roots of the spinal nerves in the frog and then injecting 
strychnine, when no convulsions occurred except when the ends of the 
cut roots were stimulated. The convulsions therefore follow only on 
the passage of an impulse from without to the spinal cord, and are 
merely a further development of the preceding stage of exaggerated 
reflex irritability. The characteristic feature of strychnine poisoning 
is thus the response to external stimuli. In the unpoisoned animal 
the reflex movement following a stimulus is always of the same kind ; 
for example, if the leg of a decapitated frog be dipped in acid it makes 
certain movements to withdraw the limb, and no matter how often the 
irritation be repeated, the same movements are produced, though it is 
true that if stronger acid be used the movement is more violent and a 
greater number of muscles are involved. In this movement certain 
muscles contract while their antagonists are inhibited, for example 
in drawing the toe away from an irritant the anterior muscles of the leg 
contract, while the gastrocnemius is relaxed. The same irritation which 
produced in the unpoisoned animal a simple withdrawal of the limb 
causes after strychnine stronger and more extensive contractions, and 
the movement is not confined to the two hind legs but spreads over the 
whole body. All the muscles contract together, there being no in- 
hibition of antagonists and the resultant movement has thus quite a 
different result ; the gastrocnemius being stronger than the anterior leg 
muscles, the foot is extended and thrust against the irritant instead of 
being withdrawn from it. When an external stimulus is sufficient to 
cause a convulsive movement in a poisoned animal, the contraction is 
always maximal ; a stronger stimulus produces no greater effect. It must 
be remarked that the reflex response to different forms of stimuli is not 
equally altered by strychnine. The irritation of the frog's foot by very 
slowly acting substances, such as dilute acids, may be followed by an ordi- 
nary reflex movement, while a sudden shock causes a violent convulsion. 



200 



ORGANIC DRUGS ACTING AFTER ABSORPTION. 



Fig 



Many attempts have been made to define the exact seat of the strych- 
nine action in the spinal cord and although the question is not abso- 
lutely determined, there are strong grounds for the belief that the cells 
of the anterior horn are not necessarily involved in the strychnine 

action. (Fig. 15.) For when strych- 
nine is applied in solution to the cord of 
the frog at the level of the cells connected 
with the nerves to the fore limbs, irrita- 
tion of the foot produces an ordinary re- 
sponse in the hind limbs, while the anter- 
ior part of the body remains motionless ; 
that is, strychnine has not penetrated to 
the cells connected with the hind limbs. 
Irritation of the fore limbs, on the other 
hand, produces tetanus not only of these, 
but also of the hind limbs, although the 
motor cells of the hind limbs have been 
shown to be outside the poisoned area. 
Tetanus can, therefore, be produced in 
parts whose motor cells are unpoisoned, 
yet the increased strength of the con- 
traction would seem to point to an affec- 
tion of these cells. The explanation 
may be that the impulse reaching the 
motor cell is stronger, and that the 
latter simply transmits this more power- 
ful impulse as it would a weaker one. 
A theory that covers the phenomena 
hitherto recognized is that the impulse 
traveling up a nerve in an unpoisoned 
frog may pass through a large number 
of paths in the cord, but meets with 
resistance in all save one. It therefore 
passes along the path of least resistance, 
and produces a definite result by acting 
on a fixed series of nerve cells. After 
strychnine the same impulse reaching the 
cord finds all the paths equally easy, and, 
therefore, divides and affects a very much 
larger number of motor cells. At the 
e same time less energy is spent in passing 
motor ceils f' f', which are under the through resistance, a greater force re- 

mfluence of the poison, but also m those . & i i i n 

supplied by ff, which have been shown mains to be expended on the motor cells, 

to be free from the strychnine action. , , . , . . . , n 

and the muscular movement is, therefore, 
much exaggerated. It is quite impossible at present to state the exact 
point at which strychnine removes the resistance to the passage of 
impulses. It does not seem located in the cells of the anterior horn, for, 
as has been mentioned, tetanus may be elicited when they are certainly 




Diagram of the spinal cord of the frog. 
A-B, the part of the cord exposed to 
strychnine. B-C, the unaffected zone. 
An impulse reaching the cord through the 
sensory fibre F passes to the motor cells 
i^and induces an ordinary reflex move- 
ment, showing that the cells FF are not 
altered by strychnine. On the other hand, 
an impulse reaching the cord through the 

isory fibre T) causes tetanic convulsions 



STRYCHNINE— NUX VOMICA. 201 

not affected by strychnine. On the other hand, the cells of the spinal 
ganglion are not requisite, for stimulation of the posterior root sets up 
tetanus in frogs poisoned with strychnine, in which the section of the root 
has thrown the spinal ganglion out of action. The poison must, there- 
fore, act at some point between the entrance of the sensory root into the 
cord and the motor cells. 1 It must be remarked that while the resist- 
ance is much reduced, it is not entirely removed and the ordinary path 
is still somewhat more easily traversed than the others, for very weak 
irritation often causes an ordinary reflex response in the frog, while 
slightly stronger stimulus throws it into opisthotonos. Baglioni has 
recently shown that a single stimulus is not sufficient to cause complete 
tetanus, but that the movement induced by the first shock leads to 
secondary stimuli arising from the joints and tendons which are moved • 
the arrival of these secondary stimuli in the cord maintains it in 
activity, and the muscles consequently remain contracted until the 
cord is fatigued and refuses to react to the persistent stimuli from the 
periphery. The muscles then relax and an interval of quiescence fol- 
lows until the cord has recovered its irritability. 

Besides the spinal cord, all other regions in which simple reflex can 
be produced are affected by strychnine. Thus the medullary centres 
are thrown into the same condition, and their responses to stimuli are 
equally exaggerated ; but they are in constant receipt of impulses, and 
strychnine by increasing the efficiency of these augments the tone of 
the medulla oblongata, when it is given in small quantities. The in- 
creased activity of the higher reflex areas may in fact lessen or inhibit 
the irritability of the cord, so that the reflex response from the latter 
may be strengthened by the removal of the brain and medulla oblon- 
gata. 

Artificial respiration has been shown to delay the onset of convul- 
sions in animals, and Osterwald has recently proved that the same effect 
may be obtained by the inhalation of oxygen ; animals survive a dose 
considerably higher than that ordinarily fatal if they are placed in an 
oxygen chamber. 

The stimulation of the spinal cord by strychnine is followed by de- 
pression and paralysis. Even during the first stage the stimulation is 
mixed with depression, for though a more violent response is induced 
by a sensory stimulus, this cannot be repeated so often as in the nor- 
mal frog, as the cord becomes fatigued more readily. The sensory part 
of the spinal cord seems to be paralyzed somewhat earlier than the 
motor cells, but these also lose their irritability after a time and no 
further movement can be elicited either by reflex or by direct stimu- 
lation of the cord. 

Strychnine seems to have no direct action on the voluntary Muscles ; 
it is stated that minute quantities increase their tone, that is, render 

1 The nuclei of the cells of the anterior horn in the spinal cord have been found 
somewhat enlarged in frogs poisoned with strychnine, but this is observed also after 
electric stimulation, and seems to indicate hyperactivity of the cell, which need not 
necessarily be due to direct action of the poison on it. 



202 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

them more tense, so that they are prepared for immediate contraction, 
but this is due to action on the cord and not on the muscle fibres. 

The Terminations of the Motor Nerves are paralyzed by large doses 
of strychnine in the same way as by curara. This effect is scarcely 
seen in mammals, as central paralysis always precedes it and destroys 
life, but in some species of frogs the nerve ends are paralyzed before 
the central nervous system. This paralysis is not due to the exhaus- 
tion of the nerve ends through the tetanus, but is a direct action on the 
terminations, although the exhaustion may contribute to the result. 

The Respiration is quickened and deepened by small quantities of 
strychnine, the action on the centre being exactly parallel to that on 
the spinal cord. 1 During the convulsions, the breathing is arrested by 
the violent contraction of the diaphragm and the other respiratory 
muscles, but during the intermissions it continues fairly regular. 
After one or two spasms it often fails to be reinstated, and the animal 
dies of asphyxia ; in other experiments it undergoes a gradual diminu- 
tion in rate and strength, and eventually ceases from gradual paralysis 
of the centre. 

Fig. 16. 




The blood-pressure tracing of a cat under strychnine, showing the marked rise during a spasm. 
A, quiescence ; B, convulsion commencing. 

In frogs very large quantities slow and weaken the Heart by direct 
action, but in mammals it is not directly affected by strychnine, though 
the stimulation of the inhibitory centre leads to a slightly slower 
rhythm. Occasionally acceleration of the heart is seen during and 
after a convulsion, and this is probably due to the muscular exertion, 
and may be compared to that seen after violent movements in ordinary 
life. The stimulation of the Vaso-motor Centre leads to a constriction 
of the peripheral arterioles. Strychnine in small quantities therefore 
slows the heart and raises the blood-pressure, unless in exceptional 
cases where the slowing of the heart is so great as to counteract the 
contraction of the arterioles. 

1 According to Impens (Arch, internat. de Pharmacodyn. , VI., p. 156), this occurs 
in the rabbit only when sufficient strychnine is injected to cause spasms. 



STRYCHNINE— NUX VOMICA. 203 

Daring the convulsions the blood-pressure is raised to an extreme 
height, partly owing to the activity of the vaso-motor centre and per- 
haps partly from the blood being pressed out of the abdominal organs 
and the muscles by their violent contraction. Immediately after a 
convulsion the blood-pressure falls, probably from the exhaustion of 
the centre. The blood -pressure remains elevated much longer in cura- 
rized than in uncurarized animals, which would seem to indicate that 
the fall in pressure is partly due to the substances produced by mus- 
cular activity. The constriction seems to affect mainly the internal 
vessels, while those of the skin and perhaps of the muscles are dilated, 
and the blood current is, therefore, deflected largely from the internal 
organs to the skin and limbs. The cause of the dilatation of these 
vessels is probably stimulation of vaso-dilator areas in the medulla. 

The heart continues to beat long after the breathing has ceased, and 
if artificial respiration be had recourse to, may remain active an in- 
definite time. 

In the Alimentary Tract, strychnine has the same action as any other 
bitter substance, and it produces a flow of saliva and increased appetite 
if taken before meals. (See Stomachic Bitters, page 55.) It seems 
to be absorbed from the intestine mainly. After absorption it probably 
increases the activity of the central apparatus regulating the movement 
of the bowel, but the results in man and in most animals have not been 
ascertained with exactness. 

Metabolism. — Strychnine produces an enormous activity of the mus- 
cles, and, therefore, increases very greatly the consumption of oxygen 
and the output of carbonic acid. This increased excretion of carbonic 
acid occurs, though to a less extent, even when the muscular contrac- 
tion has been previously eliminated by curara, and must, therefore, be 
due in part to the contraction of the involuntary muscle of the vas- 
cular walls and perhaps to the increased metabolism of the central 
nervous system. 

The augmentation of the oxidation in the tissues is accompanied by 
an increased formation of heat, which would lead to a rise in the tem- 
perature of the body were it not counteracted by an equal or even 
greater increase in its dissipation through the skin. The result of the 
interaction of these two factors is that in spite of an increased warmth 
production the internal temperature is generally lowered in rabbits, 
while a slight rise in the thermometer is sometimes seen in dogs and 
cats. The skin temperature, on the other hand, rises considerably 
because more blood flows through it than usual. 

In the frog, the administration of strychnine is often followed by 
glycosuria. This does not seem to occur in adult mammals but is 
sometimes observed in young dogs, in which, as in frogs at certain 
seasons, there is a large accumulation of glycogen in the liver. Demant 
states that strychnine, even in small quantities, causes the glycogen of 
the liver and muscles to disappear; the increased muscular movement 
and the disturbance of the respiration are probably the explanation of 
both of these phenomena. 



204 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

Strychnine is eliminated in the urine chiefly. Its excretion begins 
soon after its injection, but is exceedingly slow, and the reaction is 
often given by the urine for 3-8 days afterwards. Traces of the alka- 
loid also appear in the stomach after its hypodermic injection, and it is 
not improbable that some of it undergoes oxidation in the tissues. 

The statement that a tolerance can be acquired for strychnine when 
it is given for some time has been proved quite incorrect (Hare). 

The action of strychnine is almost identical throughout the vertebrate 
kingdom. Man is more susceptible than other mammals, and young ani- 
mals are more refractory than adults, perhaps owing to the less developed 
condition of the central nervous system. The domestic fowl tolerates com- 
paratively large quantities without symptoms. Among the invertebrates, 
the reaction to strychnine seems to vary considerably ; in the medusae 
symptoms of increased irritability and typical convulsions are produced by 
it (Romanes), while in the crab slightly increased movement may be observed 
occasionally, but the chief effect seems to be depression and eventual 
paralysis. The snail is said to be practically immune. The temperature of 
the animal has some influence on the action of the poison, for frogs react 
more readily when heated than when kept in the cold, the heat seeming to 
increase the activity of the central nervous system. 

Brucine, the second alkaloid of nux vomica, resembles strychnine closely 
in action but is much weaker, from 30 to 40 times as large a dose being re- 
quired to produce the same effect. It differs from strychnine also in possess- 
ing a much more powerful action on the nerve terminations in voluntary 
muscle, especially in some species of frog. It is credited with weak local 
anaesthetic properties. 

Calabarine and gelsemine are chiefly of interest as impurities which 
occur along with the more important alkaloids of the Calabar bean and of 
Gelsemium, while thebaine forms a connecting link between the opium alka- 
loids and strychnine, and will be discussed along with the morphine series ; 
it seems to stand midway between strychnine and brucine in toxicity. 

Preparations. 

Nux Vomica (U. S. P., B. P.), the seeds of Strychnos nux-vomica, contains 
0.9-2 per cent, of strychnine and 0.7-1.5 per cent, of brucine, along with 
tannin, which gives a dark green coloration with iron salts. The powdered 
bean is occasionally prescribed in doses of 0.06-0.25 G. (1-4 grs.). 

Extractum Nucis Vomicae (U. S. P., B. P.), 0.015-0.06 G. {\-l gr.). 

Extraction Nucis Vomicae Fluidum (U. S. P.), 0.06-0.3 c.c. (1-5 mins.). 

Extractum Nucis Vomicae Liquidum (B. P.), 1-3 mins. 

Tinctura Nucis Vomicae (U. S. P., B. P.), 0.3-1 c.c. (5-15 mins.). 

Strychnina (U. S. P., B. P.), 0.002-0.004 G. (uWo gr.). 

Strychnine Sulphas (U. S. P.), 0.002-0.004 G. (3V1V gr.). 

Strychnine Hydrochloridum (B. P.), eV-iV g r - 

Liquor Strychainse Hydrochloridi (B. P.) (1 per cent.), 2-8 mins. 

Ferri et Strychninx Citras (U. S. P.), 0.06-0.2 G. (1-3 grs.). 

Syrupus Ferri, Quininae, et Strychninx Phosphatum (U. S. P.), 4-8 c.c. (1-2 
fl. drs.). 

Syrupus Ferri Phosphatis cum Quinina et Strychnina (B. P.), £-1 fl.- dr. 

The extract is generally prescribed in pill form, while strychnine sulphate 
or hydrochlorate may be given in solution, pill or tablet ; where rapid action 
is desired, it is injected subcutaneously. The tincture is largely used as a 
stomachic bitter, and the iron preparations in conditions of general debility. 

Ignatia, the seed of Strychnos Ignatia (St. Ignatius bean), was formerly 
included in the U. S. P., but has been excluded from the last edition. 



STRYCHNINE— NUX VOMICA. 205 

Brucina is not pharmacopceial but is sometimes prescribed in doses of 
0.005-0.03 G. ( r W gr.)- 

Therapeutic Uses. — Strychnine is used largely for its local action on 
the digestive organs as a stomachic bitter, and is generally prescribed 
in the form of the tincture or one of the extracts for this purpose, as 
in this way it is much less liable to absorption than when given as an 
alkaloidal salt. It may be combined with the cinchona preparations 
or with one of the simple bitters. 

Small quantities of strychnine are of benefit in many ill-defined con- 
ditions of weakness, cachexia and " want of tone " generally. The 
results are probably partly due to its stomachic effects in increasing 
appetite and digestion, but the action on the central nervous system 
cannot be overlooked. The slight increase in the irritability of the 
cord probably leads to an improvement in almost all of the nutritive 
functions through increasing the contraction of the vessels and pro- 
ducing greater activity of the muscles. In this way strychnine per- 
haps deserves the name of " tonic " more than most of the drugs to 
which it is applied. 

As a stimulant to the central nervous system ' strychnine has found 
wide application in almost every form of paralysis, and as long as dis- 
tinct anatomical lesions of the central nervous axis are absent, it may 
be of benefit ; for instance, it is often valuable in lead poisoning ; but 
where the continuity of the axis is broken by haemorrhage or by the 
destruction of the nerve cells, little improvement is to be anticipated 
from its use, though it may serve to delay or prevent the atrophy of 
peripheral nerves and muscles in some of these cases. When the par- 
alysis is due to an inflammatory process, strychnine is to be used with 
the greatest care, or is perhaps better avoided entirely as long as the 
irritation is present, as it seems to increase and prolong the inflamma- 
tion when used early in these cases. 

Strychnine is used as a respiratory stimulant in some forms of pul- 
monary disease in which it is desirable to increase the respiration or to 
provoke coughing. It has been advised in failure of the respiration 
during anaesthesia, and is certainly more likely to be beneficial than 
the great majority of drugs suggested for this purpose. Too large 
doses must not be injected in these cases, however, as strychnine 
paralyzes the respiratory centre itself when given in excess. In other 
forms of poisoning in which the respiratory centre seems in danger, 
and in shock, strychnine may also be of service, especially when it is 
injected hypodermically. Other respiratory stimulants winch may be 
substituted for strychnine for some purposes are caffeine and atropine. 

In amaurosis or amblyopia unassociated with atrophy of the optic 
nerve, and even in commencing atrophy, strychnine has frequently im- 
proved the vision. In many cases it fails to produce any benefit, and 
the exact conditions in which improvement can be looked for are un- 
known. 

1 Other central nervous stimulants are Caffeine, Atropine. 



206 ORGANIC DRUGS ACTING AFTER ABSORPTION 

Strychnine seems to be of benefit in some cases of heart disease 
and is often supposed to have a direct action on that organ. Any im- 
provement which may be produced by it, however, must be attributed 
to the constriction of the vessels, and the indications for its use would 
seem to be a low blood-pressure. The increased arterial tension may 
be prejudicial to the heart in some conditions, through increasing the 
resistance against which it has to contract. The heart rhythm is also 
slower after strychnine has been administered, owing to stimulation 
of the inhibitory centre. A similar effect follows the use of aconite, 
veratrum, and digitalis, though in the case of the last it is accompanied 
by changes in the heart which are not induced by the others. 

Strychnine is said to be of value in chronic alcoholism in lessening the 
depression which forms one of the chief difficulties in the treatment. 

The other alkaloids of this series do not seem to have any proper- 
ties w 7 hich would entitle them to a position in therapeutics. 

Poisoning. — In cases of strychnine poisoning, the first treatment 
consists in the evacuation of the stomach by means of emetics, or bet- 
ter by the stomach tube ; it may be necessary to give chloroform as the 
attempt to pass the tube is. often followed by violent convulsions. 
Preparations of tannic acid, such as strong tea, may be given in order 
to form the insoluble tannate, which, however, must be removed as 
quickly as possible, as it is broken up by the acid gastric juice and 
the strychnine is rapidly absorbed. To combat the convulsions, de- 
pressants to the central nervous system should be given, and, although 
chloral is usually advised, chloroform or ether is often preferable. 
It is unnecessary to produce deep anaesthesia, a few whiffs of chloro- 
form being often sufficient to allay the convulsions. The advantage 
of the anaesthetics over chloral is that they can be removed if any 
symptoms of strychnine paralysis appear. Opium has been suggested, 
but is not nearly so efficacious in strychnine poisoning as members of 
the methane series. If the paralysis comes on, artificial respiration 
may be attempted, although the poison is excreted too slowly from 
the organism to permit of much hope of recovery. 

BlBLIOGEAPHY. 

Mayer. Sitzungsber. der Wiener Acad., lxiv., 1871, p. 657. 
Denys. Arch. f. exp. Path. u. Pharm., xx., p. 306. 
Falck. Volkmann' s Sammlung Klinischer Vortrage, No. 69. 
Ponlsson. Arch. f. exp. Path. u. Pharm., xxvi., p. 22. 
Wood. Journ. of Physiol., xiii., p. 870. 
BiernacH. Therap. Monatsheft, 1890, p. 383. 
Berkhnlz. Dissertation, Dorpat, 1893. 
Fodera. Arch. Ital. de Biol., xvii., p. 477. 
Barnack. Centralbl. f. Physiol., 1898-99, p. 621. 

Wertheimer et Delezenne. Comptes rendus de la Soc. de Biol., 1894, p. 632. 
Delezenne. Arch, de Physiol. (5), vi., p. 899. 
Houghton and Muirhead. Medical News, 1895, i., p. 612. 
Reichert. Med. News, 1893, i., p 369. 
Mays. Journal of Phys., viii., p. 391. 
Hogyes. Arch. f. exp. Path. u. Pharm., xvi., p. 97. 
Walton. Journal of Phys., iii., p. 308. 
Hebdom. Skand. Arch. f. Phys., ix., p. 45. 



OPIUM SERIES. 207 

Filehne and his pupils. Pfliiger's Archiv, lxxxiii., pp. 369, 397, 403. 

Singer. Arch. f. Ophthalmologic, 1., p. 665. 

Osterwald. Arch. f. exp. Path., xliv., p. 451. 

Verworn and Baglioni. Arch. f. [Anat. u.] Phys., 1900, p. 385, Supplem., pp. 152, 
193. 

Meltzer and Salant. Journ. of Exp. Medicine, vi., p. 107. 

Hare. Amer. Journ. of Physiol., v., p. 333. 

In addition, strychnine was studied by Magendie, CI. Bernard and Orfila and thei; 
works ought to be consulted for the earlier history of the poison. 

III. OPIUM SERIES. 

Opium has been used in medicine since a very remote period, and 
although many substitutes have been proposed for it of late years, it 
still occupies a position of its own in therapeutics. It is the dried 
juice of the Papaver somniferum, a poppy which is grown chiefly in 
India, China, Egypt, Persia and Asia Minor, but has been cultivated 
in colder climates and is said to produce a more powerful opium 
there. Opium owes its activity to a large number of alkaloids, of 
which Morphine is the most important. Others are Codeine, Pseudo- 
morphine, Thebaine, Codamine, Laudanine, Laudanosine, Papaverine, 
Meconidine, Lanthopine, Cryplopine, Protopine, Papaver amine, Rhcea- 
dine, Narcotine, Oxynarcotine, Narceine, Hydrocotarnine, Gnoscopine 
and Tritopine. Many of these, however, occur only in traces. The 
total amount of alkaloids in opium varies from about 5-25 per cent., 
and different specimens may contain very different quantities of each 
alkaloid ; for instance, morphine may vary from 2.7-22.8 per cent. 
The average percentage of morphine is 10, of narcotine 6, papaverine 
1, codeine 0.5, thebaine 0.3 and narceine 0.2 ; the others occur in too 
small quantity to have any influence on the action of the crude drug. 
The alkaloids are found in opium in combination with meconic, lactic 
and sulphuric acids. The empirical formulae of most of the alkaloids 
have been determined, those of the most important being morphine 
(C 17 H 19 N0 3 ), codeine (C 18 H 21 N0 3 ), narcotine (C 22 H 23 NO_), papaverine 
(C 20 H 21 NO 4 ), thebaine (C 19 H 21 N0 3 ). The constitutions of several are 
known, and these appear to be isoquinoline derivatives, but the structural 
formulae of morphine and codeine are still undecided, and the majority 
of investigators are now inclined to believe that they do not belong to 
the pyridine-quinoline alkaloids. Morphine apparently contains phe- 
nanthrene (C U H 10 ), a hydrocarbon isomeric with anthracene, combined 
with a nitrogenous radicle which is probably morpholine ; l it possesses 
two hydroxyls and the substitution of one of these by methoxyl forms 
codeine. Thebaine and several others appear to be closely related to 
morphine, and it is not improbable that they may all eventually prove 
to be more nearly related than their reactions would seem to indicate 
at present. 

The action of opium is due to the large amount of morphine con- 

1 The formula for morphine accepted as most probable at present is 

c u h 10 (OH) 2Xo • 



208 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

tained in it, the other alkaloids being present in too small quantity to 
modify its effects appreciably. Morphine acts chiefly on the central 
nervous system although it also affects some peripheral organs, such 
as the intestine. Its action varies considerably in different animals, 
and it is therefore necessary to consider its effects at some length upon 
the different classes. 

Symptoms. — The Frog is remarkably tolerant of morphine, no change 
whatsoever following the injection of quantities which would cause dis- 
tinct symptoms in man. The first symptoms elicited are a diminution 
of the spontaneous movements ; the animal sits still unless disturbed, 
but then moves in a perfectly normal manner. Later the movements 
become clumsy and ill-coordinated, and at the same time they are 
elicited less easily. At a somewhat more advanced stage of the intox- 
ication, the animal makes no movement when placed in abnormal 
positions, as on its back, which indicates that it has lost entirely its 
power of preserving its equilibrium. The spinal cord maintains its 
irritability, but in a lower degree than usual, as is shown by the reflex 
movements being weaker than in the unpoisoned frog. This condition 
may last for several hours, when a series of symptoms of an entirely 
different nature appear. The reflex response to irritation is distinctly 
depressed during the first stage, but in this second phase it begins to 
return, and eventually a condition of exaggerated reflex irritability 
sets in. This development first affects the muscles of respiration, 
but soon spreads over the whole spinal cord, so that the condition 
comes to resemble exactly that noted in strychnine poisoning, except 
that the frog seems more easily exhausted than after moderate quanti- 
ties of strychnine. The same tetanic contractions of the muscles are 
to be seen, how T ever, with opisthotonos and cessation of the respiration, 
interrupted by periods of quiescence and exhaustion. The animal 
may recover from this stage, in which case it again passes through the 
stage of depression, but it frequently dies during it from exhaustion 
and paralysis of the central nervous system. 

In Mammals, morphine produces symptoms resembling those seen in 
the frog, first depression of the voluntary movements, and later a marked 
increase in the reflex irritability. The relative importance of these two 
stages differs, however, in the different classes, and indeed in different 
individuals of the same class. Thus in the cat and in all the other 
felidse, and in the horse and ass morphine seems rather to increase than 
to diminish movement. The animal runs about the room or in a circle 
and seems unable to remain at rest for a moment. At the same' time a 
depression of the intelligence and of the power of perception makes it- 
self manifest, for no definite attempts at escape are made and obstacles 
are not avoided so carefully as by the unpoisoned animal. Eventually 
convulsions similar to those seen after strychnine are developed. In 
the dog, on the other hand, the depressant action of the drug is the more 
highly developed, at any rate after small doses. The first symptom is 
not infrequently vomiting and defsecation, and then the animal passes 
into a light sleep, from which he can be easily aroused by touching or 



OPIUM SERIES. 209 

by noise, but which rapidly becomes deeper, so that greater force has 
to be used to waken him. Wheu once awakened, he seems to sleep less 
heavily for a short time, and a much slighter stimulus is enough to 
arouse him if it is applied soon afterwards. When awakened he may 
perform apparently voluntary movements for a short time, although 
more clumsily than in his normal state, but no complete conscious- 
less is present, the animal is stupid and drowsy and soon sinks back 
into deep slumber again. The sensation of pain seems to be much 
lessened but not entirely abolished, and reflex movements are diffi- 
cult to elicit. After larger quantities an exaggerated sensibility to 
external stimulation seems present, for the animal starts convul- 
sively at loud sounds and on pinching, but when left undisturbed lies 
in profound sleep. The respiration is at first quick and dyspnceic, the 
dog panting as if after a long run, but later it becomes slow and 
labored ; the pupil is narrowed ; the circulation seems less affected, 
although a congestion of the skin and mouth is often observed. The 
stage of strychnine-like convulsions is not developed in the dog, 
although the reflex irritability may be distinctly increased by large 
quantities. Just before the respiration finally ceases, convulsions 
generally occur, but these are asphyxial in origin and are not due to 
the direct action of the alkaloid. In the rabbit and other rodents the 
symptoms are similar to those seen in the dog, but the depression is 
even more marked. An increase in the reflex irritability to external 
stimulation is also evident here, while the respiration is slowed from the 
beginning. Small quantities of morphine produce drowsiness in the 
horse, ass or goat, larger quantities restlessness and excitement which 
may pass into convulsions and death. Harley found excitement and 
subsequently coma and death produced by morphine injections in the 
mouse. 

In Birds, morphine causes vomiting, drowsiness, sleep and stupor, 
with slow and imperfect respiration, very much as in mammals. It 
has been repeatedly stated that pigeons possess a high degree of toler- 
ance for morphine, but this does not seem correct, for though in com- 
mon with all the lower animals they are much less susceptible to its 
influence than man, the tolerance does not seem much greater than that 
of rabbits and dogs when the drug is administered hypodermically. It 
seems to be absorbed with difficulty from the crop. 

In Man, small quantities of morphine lessen the voluntary move- 
ments and produce a drowsiness which soon passes into sleep, unless 
the patient is continually aroused by his surroundings. As long as he 
is kept awake, his actions and movements show nothing abnormal, but 
it is impossible to keep his attention directed to any object for long, 
and as soon as he is left to himself for a few moments he sinks into 
sleep. After small quantities there is no difficulty in arousing him ; in 
fact, the sleep seems lighter than usual and may resemble rather a 
state of abstraction or "brown study"" In this condition the im- 
agination is not depressed to the same extent as the reason, and it is 
often stated, therefore, that opium at first stimulates the intellectual 
14 



210 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

powers. This is incorrect, however — the self-control and judgment 
are lessened, and although the stream of thought may seem more rapid 
and the images more vivid than usual, the logical sequence is lost, and 
the condition may rather be compared to dreaming than to a real in- 
crease of the intellectual powers. In particular, the patient has often 
no idea of time. This stage of abstraction is not by any means gen- 
erally observed and soon passes into sleep, but the unchecked imagina- 
tion may still persist in the form of dreams. 

In larger quantities morphine produces deep, dreamless sleep, from 
which the patient is still easily aroused, but which returns at once 
when he is left undisturbed. When once aroused, he can be kept 
awake or can be aroused again after a short interval much more easily, 
some time elapsing apparently before the same degree of depression is 
reached again. As the dose is increased, the sleep deepens into torpor, 
from which he can be wakened only with difficulty, and eventually all 
efforts to arouse his attention are fruitless and he sinks into coma, 
which may be reached very soon after a large dose.. During this 
deeper sleep and coma the respiration is very slow, the pulse is regu- 
lar, full, and of moderate speed. The pupils are contracted to a small 
point and the mouth and throat are dry. The face is purple and con- 
gested, and the skin feels warm, although the temperature may be low. 
The breathing generally becomes slower and weaker, and occasionally 
periodic (Cheyne-Stokes). The cyanosis increases, the pulse becomes 
smaller and often quicker, the pupils remain contracted, but dilate 
widely just before the final arrest of the repi ration. The heart con- 
tinues to beat feebly for a short time afterwards. 

After small doses of morphine the patient generally awakes refreshed, 
and, save for an occasional dryness of the throat and slight nausea, 
apparently quite normal. Not infrequently, however, headache is com- 
plained of, and sometimes nausea and vomiting, accompanied by marked 
depression. In rare cases delirium, and even convulsions, have been 
observed soon after its injection, but these symptoms of excitement are 
so rare in the human subject as to be classed as idiosyncrasies. Some 
skin affections, such as itching and redness, are occasionally seen while 
the action is passing off. 

Action. — The action of morphine on the Central Nervous System seems 
to consist then of a mixture of stimulation and depression, which are 
not equally marked, however, throughout the divisions of the central 
axis. The depression seems to be produced mainly in the brain, 
especially in those parts associated with the higher intellectual facul- 
ties, while the stimulation affects first the spinal cord. It seems likely 
that in different animals these two opposing influences prevail to vary- 
ing extents, so that in some the stimulant action extends to the brain, : 
as in the cat, while in man the depressant action dominates the whole 
central nervous system, at any rate when moderate quantities are used. 
The action on the brain is elicited by smaller quantities than that on 
the cord, so that the first effect of morphine is general intellectual de- 
pression, while the increased activity of the spinal functions is only 



OPIUM SERIES. 211 

elicited by very large quantities. This selective action of morphine is es- 
pecially evident in the medulla oblongata, in which certain centres are en- 
tirely paralyzed before neighboring ones undergo any distinct modi ligation. 

Morphine, therefore, seems to combine in itself the properties of 
alcohol and of strychnine ; like the former, it depresses the functions 
of attention and coordination of the brain, while, like the latter, it in- 
creases the activity of the spinal cord. 

The effect of morphine on the Spinal Cord has been studied almost 
exclusively in the frog. The reflex irritability in these animals is first 
diminished to a slight extent, and then increased to the same degree 
as by strychnine. It seems difficult to believe that the same drug 
should cause first depression and then stimulation of a function, but it 
has been shown in the description of the action of strychnine that all 
the elements of the spinal cord are not involved in the changes pro- 
duced by that poison, and a possible explanation would be that while 
small quantities of morphine lessen the ability of the motor cells to 
give out impulses, larger quantities increase the activity of the recep- 
tive and transmitting cells, so as to compensate for the depression of 
the motor cells and eventually to conceal their depression entirely. 

It will be shown in the discussion of the effects of morphine on the 
respiratory centre that some grounds exist for the belief that the 
motor functions are depressed by morphine, but this explanation of its 
action on the cord must be looked upon merely as a preliminary hypoth- 
esis to account for the phenomena. 1 

The hypothesis of opposing action on the motor and sensory ele- 
ments of the cord would explain the different results observed in dif- 
ferent classes of animals by assuming that the depressant effects on 
the motor apparatus are more developed in one class, while in another 
the stimulation of the receptive apparatus is the predominating feature. 
It is to be remarked that in all animals the cord is less depressed than 
in the corresponding stage of chloral poisoning, for if two animals are 
poisoned, the one with morphine, the other with chloral, until no 
voluntary movements occur, the reflexes of the one poisoned with 
morphine are always found more active than those of the other. 

The effects of morphine on the Brain are no less difficult to account 
for than those on the cord. In the frog, the symptoms of increasing 
depression correspond to those observed after the removal in succession 
of the cerebral lobes, the corpora quadrigemina, the cerebellum and 
the medulla oblongata. In man, it is often found that comparatively 
small quantities are sufficient to deaden or even entirely remove the 
pain of disease without rendering the patient unconscious. The in- 
telligence is not so acute as normally, but he answers questions and 
converses freely and may even seem abnormally sensitive to impres- 
sions caused by loud noises or bright flashes of light. Animals in this 
condition may be subjected without resistance to what would ordi- 

1 The old explanation, which attributed the increased activity of the spinal cord to its 
hcinu' liberated from the inhibitory action of the brain through the cerebral depression, 
lias proved inadequate, for total destruction of the brain docs not give rise to the ex- 
aggerated reflex movements elicited by morphine in the frog. 



212 



ORGANIC DRUGS ACTING AFTER ABSORPTION. 



Fig. 17. 



narily involve considerable pain, provided the application be not sud- 
denly made. If struck suddenly, however, they react as usual, and 
remain apparently as sensitive as usual for some time. Morphine 
then seems to lessen the power of concentrating the attention. As 
long as any stimulus is of constant strength, be it an internal pain or 
a noise or light, the morphinized individual remains unconscious of it. 
On the other hand, a shock is at once perceived, and the lethargy being 
for the moment dispelled, he reacts to his surroundings for a short time, 
but is incapable of prolonged attention and soon sinks into stupor again. 
Morphine in moderate quantities seems to have but little effect on 
the irritability of the motor areas of the brain cortex, but in large 
quantities it lowers and eventually abolishes it. Exner found no 
alteration in the time elapsing between the perception of a flash of light 
and a preconcerted movement, while others have found that the re- 
action to a slight touch was re- 
tarded. This would agree with the 
hypothesis introduced above — the 
power of attention is lessened and 
slight stimuli are, therefore, per- 
ceived more slowly, while a stronger 
impression is perceived and acted 
upon after the usual interval. 

Several observers have investi- 
gated the relative sensibility of the 
skin before and after morphine. 
The method employed was to meas- 
ure the smallest distance on the skin 
at which the person could recognize 
two points as distinct. In every 
case it was found that the ability to 
do this was lessened by morphine 
owing to the central depression, the 
drug seeming not to have any direct 
action on the sensory organs them- 
selves. Various authors have ex- 
amined the cortical cells after mor- 
phine with the hope of finding some 
histological changes produced by it. 
The results are discordant, how- 
ever, and alterations said to be 
characteristic by one investigator 
have been shown to be due to the 
histological methods used by him. 
Before closing the consideration 
of the action of morphine on the 
central nervous system, it may be well to discuss its effects on the 
Respiration. In man and in most other animals the respiration is 
slowed by morphine from the beginning (Fig. 17), but in the dog 




o 10 



Diagram of the volume of air inspired by a 
rabbit during morphine narcosis. 31, injection 
of morphine. The amount is measured in c.c. 
along the perpendicular, while the time is meas- 
ured along the horizontal line. At first about 
540 c.c. is inspired in 2% minutes, but after the 
injection of morphine, 31, the volume falls to 
about 200 c.c. and is maintained at 200-300 
throughout the experiment. (After Sturs- 

BEEG.) 



OPIUM SERIES. 213 

there is often a preliminary stage of rapid, panting breathing, which 
may, however, be secondary to the emetic and purgative effects. The 
respiration in man is at first somewhat deeper than usual, but the in- 
crease in the depth is not sufficient to counterbalance the slowness of 
the breathing, so that the air inspired per minute is considerably re- 
duced ; in the later stages it becomes shallower and is often irregu- 
lar. This irregularity may have a periodic character, a series of deep 
respirations being followed by several progressively weaker ones and 
then by complete inactivity for several seconds. The breathing then 
recommences with a very slight movement, followed by a series in- 
creasing regularly in strength and then again decreasing. This form 
of respiration (Cheyne-Stokes) is seen in various pathological condi- 
tions and has received different explanations, 1 but is probably due to 
direct action on the respiratory centre. It has been mentioned already 
that when the animal is once aroused repeated movements are much 
more easily elicited, and it would seem probable that the accumulation 
of carbonic acid and other poisons and the lack of oxygen in the blood 
during the pause eventually awaken the torpid centre, which causes a 
small movement. The next movement is larger owing to the persist- 
ing activity of the centre and this continues until, the blood becoming 
less venous, the stimulus becomes weaker and the cells sink again into 
their former torpor, to be again resuscitated by the increasing venosity 
of the blood. Loewy has examined with particular care the condition 
of the respiratory centre, and found that much larger quantities of car- 
bonic acid than usual were required to increase the volume of the re- 
spired air a given degree. His results may indicate that the power of 
sending out impulses as well as of receiving them is lessened by mor- 
phine, while the narcotics of the methane series may perhaps lessen the 
receptivity of the centre without lessening its power to emit impulses. 
After large doses the respiration becomes gradually slower and 

Fig. 18. 





Cheyne-Stokes respiration in opium poisoning. The up strokes denote inspiration. (After Filkiixk. ) 

weaker, and often loses its periodic character. Even after conscious- 
ness fails to be aroused by the most powerful shocks, some influence 
may be exerted on the respiratory centre. Thus the sudden application 
of cold water may cause several deep respirations, although it fails to 
dispel the stupor, but the respiration finally fails to react to these ap- 
plications and soon afterwards ceases. 

^According to Filehne, it is caused by alternate .constriction and dilatation of the 

brain vessels. 



214 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

To sum up the action of morphine on the central nervous system, 
it produces great depression which is especially marked in the psy- 
chical functions, but spreads over the lower parts of the nervous axis 
and involves sooner or later the respiratory centre. This depression 
does not seem to affect so much the motor areas as the powers of the 
will and attention. In mammals the failure of the respiration closes the 
course of the intoxication, but in the cold-blooded animals a further 
development of excessive reflex irritability follows which may pass 
into tonic convulsions. Even in the higher animals some indication 
of this action on the cord may occur, and in the feline group this stimu- 
lation involves not only the cord, but also the motor areas of the brain 
apparently. 

Morphine has little direct action on the Circulation. The heart is 
often slightly accelerated at first, perhaps from the slight nausea. 
The frog's heart is rendered slow and weak by very large quantities of 
morphine. 1 

The blood-pressure remains high and the peripheral arteries in 
general show no change of calibre, with the exception of those of the 
skin, especially of the head and neck, which are dilated, rendering the 
face flushed and hot ; as asphyxia comes on the flush becomes more 
dusky and cyanotic, but the vessels remain dilated, so that the face is 
of a bloated, purple color. The dilatation of these vessels has little in- 
fluence on the general pressure. It arises from some obscure central 
action, but it is unknown whether this is of the nature of stimulation 
or of depression. The dilatation of the superficial vessels causes a sense 
of warmth in the skin, which is occasionally followed by itching and 
discomfort. It may account in part for the increased perspiration often 
observed, although this is doubtless contributed to by other factors. 
As asphyxia advances, the pulse may become slow, while the blood- 
pressure varies, either rising from the asphyxial activity of the vaso- 
motor centre or falling from the slowness of the heart. These effects 
are entirely absent if the blood be sufficiently aerated by artificial res- 
piration, and are, therefore, to be regarded as indirect results of the 
action on the respiratory centre. 

It is asserted that the pulse is sometimes accelerated and weak be- 
fore death, but this does not seem a constant feature and has received 
no explanation, unless Gscheidlen's statement that the terminations of 
the vagus in the heart are paralyzed be accepted as sufficient to ac- 
count for it. 

The selective action of morphine is thus excellently illustrated in its 
effects on the medulla oblongata, for the respiratory centre is paralyzed 
before the centres for cardiac inhibition and vaso-constriction are 
affected to any marked extent. 

The peripheral Muscles and Nerves are also unaffected by morphine 
in any except overwhelming doses. Even when directly applied to 

1 Barnard states that the cat's heart dilates more completely and also contracts more 
strongly under morphine, but this is opposed to earlier investigations and cannot be 
received without confirmation. 



OPIUM SERIES. 215 

the nerve it has but little effect on the irritability (Waller). When mor- 
phine is injected subcutaneously in the frog in large quantities, it 
lessens the power of the end-organs to transmit impulses, but no such 
effect is noted in mammals. It is often stated that the sensory termi- 
nations are paralyzed by morphine, and solutions are therefore injected 
into the seat of pain, or liniments are rubbed into the skin over it, but 
as a matter of fact, morphine seems entirely devoid of any such local 
action. The sensibility of the skin is lowered by an injection, it is 
true, but no more so at the point of application than in other parts of 
the body, so that the action appears to be central. 

The Pupil undergoes characteristic changes in morphine poisoning. 
In the great majority of cases in man, the pupil is contracted to pin- 
point dimensions until just before the final asphyxia, when it dilates 
widely. In some animals, such as the dog and rabbit, the same effects 
are seen, while in birds the pupil remains unaffected, and in animals in 
which morphine causes movement and excitement, it is dilated widely. 
The action is undoubtedly central, and not due to any local changes in 
the eye. A number of other drugs produce equally marked contrac- 
tion of the pupil, but these have the same action when dropped into 
the conjunctival sac, while morphine has no effect when applied in 
this way; atropine applied to the conjunctiva at once removes the 
myosis produced by morphine. The terminal dilatation seen in man 
is not due to any direct action of the poison, but is a result of the 
general asphyxia. 

As a general rule the Secretory Glands seem to be rendered less ac- 
tive than usual by morphine. When it produces nausea, hosvever, it 
may increase the saliva and the mucus, but these are the usual accom- 
paniments of this condition and cannot be considered due to any special 
action of the poison. The sweat glands are exceptions to the general 
rule, however, for slight perspiration is generally observed from the 
therapeutic action, and profuse perspiration is seen before death in some 
cases in man from the effects of the asphyxia. The urine does not 
generally show any distinct alteration after morphine in man, but 
there is not infrequently retention in the bladder because the sphincter 
reflex is absent. In the dog and in some other animals, morphine 
causes glycosuria, apparently from some alteration of the glycogenic 
function of the liver. 

The Alimentary Canal manifests some distinct changes under mor- 
phine, and although these have been the subject of numerous researches 
no satisfactory explanation has as yet been vouchsafed. In the human 
subject its injection is occasionally followed by some nausea, which is 
much more frequently present, however, during recovery from the 
drug. In the dog and cat nausea and vomiting are almost invariably 
sequclse of its application in any form, and from: the rapidity with 
which they follow its subcutaneous injection would seem to be due to 
its acting on the medullary centre. Small quantities of opium or 
morphine lessen the sensation of hunger in the human subject, but tins 
is probably to be attributed to central action rather than to any effects 



216 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

on the stomach. Batelli states that the gastric movements in animals 
are first increased and then retarded by morphine, and Riegel states 
that in man and the dog the gastric secretion is generally retarded at 
first but is subsequently increased to a considerable extent. This oc- 
curs whether the drug be administered by the mouth or hypodermically 
and is therefore due to some change induced by it after absorption. 
The rate of absorption in the stomach and bowel appears to be un- 
changed by morphine. Hirsch states that the passage of the contents 
of the stomach into the bowel is delayed through a spasmodic con- 
traction of the pylorus. 

The effects on the intestine vary with the dose injected as well as with 
the species of animal. Yery large quantities cause violent peristalsis 
and repeated evacuation of the bowel in the dog, cat, and according to 
some authors, the rabbit, while small doses, on the other hand, are 
followed by lessened peristalsis and constipation in man and in most 
animals. Even in poisoning in man, the purgative effect is not ob- 
served, and opium and morphine are very extensively used in thera- 
peutics to quiet the movements of the bowel. Two explanations of 
this action have been offered, the first that moderate quantities of mor- 
phine stimulate the centre in the cord inhibiting the intestinal move- 
ments, while larger doses paralyze this centre and thus allow the bowel 
to contract more powerfully than usual (Nothnagel), the second that 
the central nervous system is not concerned in the sedative effects, 
which are attributed to morphine depressing the local mechanism in 
the intestinal wall. Neither theory is wholly satisfactory, and some 
writers are, therefore, inclined to believe that the action is partly cen- 
tral on the spinal cord and partly peripheral on the bowel wall. It is 
to be remarked that morphine is excreted by the intestinal epithelium 
and that this may have some connection with the excessive peristalsis. 
The grounds on which these explanations are founded are so involved, 
and so little convincing, that they may be omitted. 1 It seems more 
probable that the effects are peripheral than that they are central, 
however, for none of the other numerous drugs which act on the spinal 
cord possesses this curious action on the intestinal movements. 

Morphine frequently causes a. slight fall in the Temperature, which 
may be explained by the less active movements and the dilatation of 
the cutaneous vessels ; sometimes a slight preliminary rise in the tem- 
perature has been seen in man. It is found that animals under mor- 
phine react less to an increase in the surrounding temperature than 
unpoisoned ones ; i. e., a normal animal exposed to a high temperature 
takes measures to prevent its internal temperature from rising above 
the normal, while, under morphine, these measures are less effective, 
and the temperature rises more rapidly and to a greater height ; this 
indicates that the temperature centre in the brain is rendered less 
sensitive. 



1 The most recent account of the subject is that given by Vamossy, Deutsch. med. 
Wochenschr., 1897, p. 457. 



OPIUM SERIES. 217 

Metabolism. — The excretion of carbonic acid is lessened during the 
depression stage, while in those animals in which excitement is pro- 
duced, it may be considerably augmented from the increased muscular 
movement. The imperfect respiration leads to an increase in the lactic 
acid of the blood and urine and to the disappearance of glycogen from 
the liver. Sugar may appear in the urine from the same cause (Araki). 

Excretion. — Morphine is excreted mainly by the digestive tract, in the 
saliva, stomach and bowel, and is therefore found in large quantities in 
the faeces even after hypodermic injection. Traces of it occur also in 
the urine after large doses. It appears in the stomach very soon after 
injection, a weak reaction occurring after 2J minutes according to Alt, 
but after about an hour no further excretion into the stomach has been 
shown to occur, although its narcotic action persists much longer. A 
certain amount of the morphine undergoes partial oxidation in the 
tissues, and some oxidation products have been said to occur in the urine. 

Tolerance. — The continued use of morphine or opium leads to a con- 
dition of tolerance in which enormous doses of the drug are necessary 
to elicit any effect. Faust has succeeded in producing a similar state in 
dogs, and finds that much more morphine is oxidized in the tissues in 
this condition than in untreated animals ; for when a normal dog re- 
ceived an injection of morphine, over 60 per cent, of the amount in- 
jected could be recovered from the stools, while when a much larger 
quantity was injected into a tolerant animal, none whatever was found 
in the excreta. The tissues therefore acquire the power of oxidizing 
morphine when they have become habituated to its presence. 

Qxydimorphine (C ?1 H 36 N 2 6 ) has been believed to be present in the urine 
after the administration of morphine. It has also been found in opium by 
some investigators and has a very weak narcotic action resembling that of 
morphine. Marme supposed that the symptoms seen after the abrupt with- 
drawal of morphine in cases of opium habit were due to this oxydimorphine 
remaining in the tissues, but this has not been confirmed. 

Heroine is an artificial alkaloid formed from morphine by substituting 
acetyl for its two hydroxyls, and has attracted some attention recently 
through its being advocated as a respiratory sedative in cough. It appears to 
resemble morphine in its general effects, but is said to act more strongly on 
the respiration and less on the cerebral functions. Thus the respiration is 
rendered slower with less mental depression than would accompany an 
equal change elicited by morphine. According to the advocates of heroine, 
the slowness of the breathing is in part compensated for by its greater 
depth, so that the actual diminution of the air inspired is not proportional to 
the decrease in the number of the movements ; but this has been disputed 
and is certainly not invariably true, particularly in man. On the whole the 
evidence of experimental and clinical observers seems to indicate that heroine 
deserves a place between morphine and codeine. 

Codeine resembles morphine in the general features of its action, 
although it is much less poisonous. It depresses the brain, and 
causes an exaltation of the activity of the lower parts of the cen- 
tral nervous system. Its depressant action is not so powerful nor bo 
enduring as that of morphine, however, while the stimulation is more 
evident and involves not only the cord, but also the medulla oblon- 






218 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

gata and lower parts of the brain. As has been mentioned already, 
morphine also stimulates rather than depresses the brain in the 
feline class, but with codeine this is true also for the dog and to a 
less extent lor man. In the latter small quantities of codeine produce 
sleep but this is not so deep and restful as that which follows the 
administration of morphine, and the patient is liable to be awakened 
by slight noises, and is restless and often unrefreshed when he awakens. 
Somewhat larger quantities, instead of inducing deeper sleep, increase 
the restlessness and cause a considerable exaggeration in the reflex ex- 
citability. The respiration is not so much slowed as after morphine, 
and, according to Winternitz, the excitability of the centre is prac- 
tically unchanged, while morphine reduces it very considerably. The 
pupil is slightly contracted during the codeine sleep, but dilates when 
the excitement stage follows. Codeine does not seem to produce so 
great constipation as morphine, and in animals often causes purging 
and diarrhoea. It is said by Tauber to be excreted in the urine 
mainly, but his statement requires confirmation. 

Codeine is methylmorphine, and a number of similar compounds have been 
formed artificially, such as ethylmorphine and amylmorphine. Two of these, 
ethylmorphine (Dionine) and benzylmorphine (Peronine) have recently been 
introduced into therapeutics, but appear to possess no advantages over codeine. 

Papaverine stands midway between codeine and morphine in its action on 
the central nervous system, but is a comparatively weak poison. Even in 
large quantities it has not the soporific action of morphine, nor does it 
produce the same degree of excitement as codeine. Comparatively small 
quantities are followed by sleep, but this does not become deeper as the dose 
is increased. On the contrary, the reflex excitability is augmented, and 
after very large quantities some tetanic spasm may be elicited, but this seems 
to be of spinal origin entirely, while that produced by codeine points rather 
to an affection of the lower part of the brain. Papaverine has more 
tendency to slow the heart rhythm than either morphine or codeine ; it 
apparently acts directly on the heart muscle and not through the regulating 
centres. The blood-pressure is, however, little affected by ordinary quantities. 

Narcotine resembles codeine rather than morphine, but has even less 
depressant action, especially in mammals. In the frog a short stage of 
depression is elicited, but this soon gives place to strychnine-like exaggera- 
tion of the reflex excitability. In mammals there may be but little ap- 
pearance of depression, the injection being followed by a condition of ex- 
citement immediately — restlessness and tremors with increased reflexes, 
which eventually lead to convulsions, during which the animal generally 
succumbs exactly as in strychnine poisoning. The pulse is considerably 
slower after narcotine injection from a direct action of the drug on the heart. 
Narcotine is a very much less poisonous body than either morphine or 
codeine, and very large quantities have been administered repeatedly with 
little or no narcotic effect. It is a compound of hydrocotarnine, another 
opium alkaloid, with meconin. Hydrocotarnine apparently acts very much 
in the same way as narcotine, but produces even less depression. 

Narceine has attained a certain reputation owing to the statement of CI. 
Bernard that it is the most powerful narcotic of all the opium alkaloids. 
There seems, however, to be no doubt that the preparation he used was very 
impure, and that narceine itself has little or no action of any kind. It is 
exceedingly insoluble in water, and its salts are broken up in aqueous 
solution, so that it is probably absorbed very slowly and imperfectly. 

Thebaine seems to have practically no depressant action. It sometimes 
produces some heaviness and confusion in man, but this is accompanied by 



OPIUM SERIES. 219 

symptoms exactly resembling those described under strychnine, and it may 
therefore be considered as belonging to the latter series rather than to that 
of morphine ; it is very much less active than strychnine, how ever. Thebaine 
seems to differ from morphine also in its effects on the bowel, for Vamossy 
finds that it increases peristalsis instead of allaying the irritability. Lauda- 
nine seems to resemble thebaine very closely in its effects. 

The other alkaloids occur in very minute quantities in opium and pi 
no great interest from the therapeutic point of view. Very little has been 
done to elucidate their pharmacological action, but those which have 
examined seem to produce effects resembling those of the better known mem- 
bers of the group. There are some exceptions to this rule, however, for in 
the effects of Cryptopine and Protopine some features appear which seem to 
be without analogue in the action of morphine and codeine. In frogs, small 
doses produce a narcotic condition similar to that following the injection of 
morphine, but the reflex irritability does not show the same exaggeration 
afterwards ; larger quantities cause complete paralysis of the whole central 
nervous system. At the same time a very marked action appears in the 
striated muscles, the contraction of which is altered in a perfectly character- 
istic manner ; if a tetanizing series of electric shocks be passed through a 
muscle poisoned with these drugs, no real tetanus, but a series of rapid con- 
tractions and relaxations is produced. The ends of the motor nerves are also 
said to be partially paralyzed. In mammals, no depression occurs but rest- 
lessness and eventually convulsions, which do not seem to be of spinal ori- 
gin but rather suggest a stimulation to the cerebrum and midbrain. The 
heart is slow and weak, and some depression of the vaso-motor centres is 
caused by large quantities of the poisons. The respiration does not seem to 
be depressed, but rather to be accelerated, save by the largest doses. 
They paralyze the terminations of the sensory nerves on local application in 
the same way as will be described under cocaine. The action of these two 
alkaloids on muscle and on the heart would seem to separate them off 
entirely from the other opium alkaloids, although it is not impossible that 
these are merely further developments of the heart action noted after nar- 
cotine and papaverine. 

With the exception of cryptopine and protopine the alkaloids of 
opium form a series, of which morphine is one, thebaine the other 
extremity. In morphine the narcotic action is the most striking fea- 
ture, but as the successive members are taken up, this effect becomes 
less marked than the reflex stimulation, until in thebaine practically 
no depression can be made out, and the symptoms resemble those of 
strychnine exactly. Some of these alkaloids, however, differ in type 
somewhat from both morphine and thebaine, because the brain itself 
seems the seat of stimulation, and the convulsions partake more of 
the character of those produced by cocaine and atropine than of those 
of strychnine. Morphine itself possesses this action in the cat, so 
that these alkaloids do not in reality depart from the general type so 
completely as might at first appear. The more important members of 
the group may, therefore, be arranged in the following order, the most 
depressant standing first and the most stimulant last. 

Morphine (oxydimorphine). 

Papaverine. 

Codeine. 

Narcotine. 

Thebaine. 

(Strychnine.) 



220 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

In man morphine is much the most dangerous of the opium alka* 
loids, because death is produced in the narcotic stage through asphyxia. 
In most animals, however, thebaine, codeine, and laudanine are more 
toxic, because the failure of the respiration does not occur in the stage 
of depression, but during the convulsions. 

Opium itself contains besides the alkaloids already discussed, various 
acids with which they are in combination, meconic, lactic and sul- 
phuric acid, but none of these possess any action of importance. Along 
with these are found gums, sugars, albumins, wax, and the other com- 
mon constituents of plant juices, but these merely tend to delay the 
absorption of the active constituents, and cannot be said to play any 
part in the effects of opium. Of the alkaloids, morphine is present 
in greatest abundance, and is also the most powerful in its effects. 
The action of opium, therefore, is practically identical with that of 
morphine, except that the latter is absorbed more rapidly when pure 
than when mixed with the numerous inactive substances of the crude 
drug. Opium acts much more slowly than morphine, and seems to 
produce more marked effect on the intestine in which it remains for a 
longer time. It is also said to cause less nausea, although this is dis- 
puted. 

U. S. P. Preparations. 

Opium, the dried milky exudation obtained by incising the unripe cap- 
sules of Papaver somniferum, yields when moist not less than 9 per cent, of 
crystallized morphine. 

Opii Pulvis, dried and powdered opium, yielding 13-15 per cent, of 
crystallized morphine. Dose, 0.02-0.1 G. (£-l£ grs.). 

Opium Deodoratum, opium deprived of its odorous principles and of any 
other bodies soluble in ether ; sugar of milk is added to make up the weight 
to that of the original. Dose, 0.02-0.1 G. (£-l£ grs.). 

Extractum Opii, the dried aqueous extract, contains 18 per cent, of 
morphine. Dose, 0.015-0.06 G. (\-l gr.). 

The following preparations contain 10 per cent, of opium or from 1.3 to 
1.5 per cent, of morphine. 

Tinctura Opii (Laudanum). Dose, 0.3-1 c.c. (5-15 mins.). 

Tinctura Opii Deodorati. Dose, 0.3-1 c.c. (5-15 mins.). 

Vinum Opii, flavored with cinnamon and cloves. Dose, 0.3-1 c.c. (5-15 
mins.). 

Acetum Opii (Black Drop) is formed by extracting opium powder with 
dilute acetic acid. Dose, 0.3-1 c.c. (5-15 mins). 

Pulvis Ipecacuanha et Opii (Dover's Powder), 10 per cent, each of 
opium and ipecac powders. Dose, 0.3-1 G. (5-15 grs.). 

Tinctura Ipecacuanhse et Opii. Dose, 0.3-1 c.c. (5-15 mins.). 

Other preparations of opium generally weaker than the foregoing are : 

PiLUL^E Opii, each contains 0.065 G. (1 gr.) of opium powder or 0.009 G. 
(| gr.) of morphine. 

Trochisci Glycyrrhizse et Opii, each contains 0.005 G. ( T V gr.) of opium. 

Tinctura Opii Camphorata (Paregoric) contains four parts of opium 
per thousand, along with benzoic acid, camphor, oil of anise and glycerin. 
Dose, 4-15 c.c. (1-4 fl. drs.) for an adult, 0.3-1 c.c. (5-15 drops) for a 
child. 

Mistura Glycyrrhizse Composita (Brown Mixture) is formed from liquorice, 
syrup, acacia, wine of antimony, spirits of nitrous ether and camphorated 



OPIUM SERIES. 221 

tincture of opium, and contains only about 1 part of opium in 2,000. J Jose, 
15-30 c.c. {l-l fl. oz.). 

Emplastrum Opii, opium plaster, 6 per cent. 

Alkaloids : 

Morphina (C 1T H 19 N0 3 + H 2 0), colorless crystals without odor but with a 
bitter taste, practically insoluble in water and only slightly soluble in alco- 
hol. Dose, 0.005-0.03 G. (&-% gr.). 

Morphine Hydrochloras. 

Morphine Sulphas. 

Morphinse Acetas. 

Of these salts the hydrochlorate and sulphate are the most important, as 
the acetate tends to decompose on keeping. The hydrochlorate and sulphate 
are soluble in about 21-24 parts of water, less so in alcohol. They form 
white, silky crystals with a bitter taste. Dose, 0.005-0.03 G. (tV4 gr.). 

Pulvis Morphinse Compositus (Tully's Powder) is a mixture of liquorice 
powder, camphor and morphine sulphate, in which the latter is contained to 
the amount of If per cent. Dose, 0.3-1 G. (5-15 grs.). 

Trochisoi Morphine et Ipecacuanha, each contains 0.0016 G. ( T V gr.) 
of morphine sulphate. 

Codeina (C 18 H 21 N0 3 + H 2 0), white or nearly transparent crystals with a 
faintly bitter taste, soluble in 80 parts of water and in 3 parts of alcohol. 
Dose, 0.015-0.12 G. (i-2 grs.). 

B. P. Preparations. 

Opium, the juice obtained by incision from the unripe capsules of Papaver 
somniferum, inspissated by spontaneous evaporation. When dried it con- 
tains 9 1 -10 l j per cent, of anhydrous morphine, and it is therefore weaker 
than the corresponding preparation of the U. S. P. Dose, -|-2 grs. 

Extractum Opii contains 20 per cent, of morphine. Dose, J-l gr. 

Extr actum Opii Liquidum contains § per cent, of morphine (£■ gr. in 110 
mins.). Dose, 5 30 mins. 

Tinctura Opii, Laudanum, contains f per cent, of morphine, or about 1 
gr. of opium in 15 mins. Dose, 5-15 mins. for repeated administration ; 
for a single administration 20-30 mins. 

Tinctura Opii Ammoniata is formed of laudanum, benzoic acid, oil of anise 
and ammonia. It contains about \ per cent, of morphine or nearly 5 grs. of 
opium in the fluid oz. Dose, \-l fl. dr. 

Tinctura Camphors Composita, Paregoric or Paregoric Elixir, re- 
sembles the foregoing in composition except that camphor is substituted for 
ammonia and that the laudanum is reduced so that only one part of mor- 
phine is contained in 2,000 of paregoric or \ gr. of opium in each fl. dr. 
Dose, |-1 fl. dr. 

Pulvis Opii Compositus contains 10 per cent, of opium along with pepper, 
ginger, caraway and tragacanth. Dose, 2-10 grs. 

Pulvis Ipecacuanha Compositus, Dover's Powder, contain 10 per cent. 
each of opium and ipecacuanha in powder. Dose, 5-15 grs. 

Pulvis Kino Compositus contains 5 per cent, of opium along with kino 
and cinnamon. Dose, 5-20 grs. 

Pulvis Creta Aromaticus cum Opio contains 2| per cent, of opium 
along with aromatic chalk powder. Dose, 10-40 grs. 

Pilula Plumbi cum Opio contains 12| per cent, of opium along with lead 
acetate. Dose, 2-4 grs. 

Pilula Saponis Composita, contains 20 per cent, of opium. Dose, 2-4 grs. 

Pilula Ipecacuanhas cum Scilla is formed from Dover's powder and squills, 
and contains about 5 per cent, of opium. Dose, 4-8 grs. 

Suppositoria Plumbi Composita, each contains 3 grs. of lead acetate 
and 1 gr. of opium. 

Linimentum Opii (f per cent, of morphine). 



222 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

Emplastrum Opii (10 per cent, opium). 

Unguentum Gallse cum Opio contains 1\ per cent, of opium. 

Morphinse Acetas (C 17 H 19 N0 3 ,C 2 H 4 2 3H 2 0), a white crystalline or amor- 
phous powder almost entirely soluble in 2 J parts of water and in 100 of 
alcohol, }-^ gr. 

Morphine Hydrochloridum (C 17 H ]9 N0 3 ,HC1,3H 2 0), acicular prisms of 
a silky lustre, soluble in 24 parts of cold water, one part of boiling water or 
50 of alcohol. Dose £- \ gr. 

Morphinse Tartras ((C 17 H 19 N0 3 ) 2 C 4 H 6 6 ,3H 2 0), a white powder consisting 
of fine nodular tufts of acicular crystals, soluble in 11 parts of cold water, 
insoluble in alcohol. Dose, J- £ gr. 

Liquor Morphinse Acetatis, 1 per cent. , 10-60 mins. 

Liquor Morphinse Hydrochloride 1 per cent., 10-60 mins. 

Liquor Morphinse Tartratis, 1 per cent., 10-60 mins. 

Injectio Morphine Hypodermica contains 1 per cent, of the tartrate. 
Dose by subcutaneous injection, 2-5 mins. 

Suppositoria Morphine, each contains \ gr. of morphine hydrochloride. 

Trochiscus Morphine, each contains 3 V gr. of morphine hydrochloride. 

Trochiscus Morphinse et Ipecacuanhse, each contains -fa gr. of morphine hy- 
drochloride with T *2 gr. of ipecacuanha root. 

Tinctura Chloroformi et Morphinse Composita corresponds to the patented 
chlorodyne and contains 1 per cent, of morphine hydrochloride, along with 
chloroform, prussic acid, capsicum, cannabis indica, oil of peppermint and 
glycerin. Dose. 5-15 mins. 

Codeina (C 17 H 1S (CH 3 )N0 3 ,H 2 0), colorless crystals soluble in 80 parts of 
water, readily soluble in alcohol and ether. Dose, \-2 grs. 

Codeinse Phosphas ((C 17 H 18 (CH 3 )N0 3 ,H 3 P0 4 ) 2 3H 2 0), white crystals with a 
slightly bitter taste, soluble in 4 parts of water, much less soluble in alcohol. 
Dose, \-2 grs. 

Syrupus CoDElNiE, one fluid drachm contains \ gr. of codeine phosphate. 
Dose, |-2 fl. drs. 

Papaveris Capsulse, the nearly ripe dried fruits of Papaver somniferum, 
contain a small percentage of morphine, but are entirely superfluous in 
therapeutics. 

Therapeutic Uses. — Opium is one of the most important and most 
extensively used drugs in the pharmacopoeias at the present day as in 
the past. Of late years the crude drug has been largely replaced by 
morphine, but the action is the same, and although morphine is pref- 
erable in most cases, opium is still specially indicated for certain pur- 
poses. In almost any disease, conditions which are favorably influenced 
by morphine may present themselves, and these conditions alone can 
be discussed here. 

Pain. — As has been repeatedly mentioned, opium or morphine has 
a special analgesic action which is not shared by its modern rivals of 
the methane series, and which justifies the celebrated dictum of Syden- 
ham that without opium few would be callous enough to practise 
therapeutics. The general statement may suffice that severe pain in- 
dicates opium. Even where the disease in itself is one which would 
in ordinary circumstances contraindicate it, it must be always taken 
into consideration whether the relief of the pain and its attendant rest- 
lessness may not counterbalance the disadvantages of the narcotic. At 
the same time the danger of inducing the craving for morphine cannot 
be forgotten, for the use of morphine to subdue pain is perhaps the 



OPIUM SERIES. 223 

most fruitful cause of the habit. It is often found that comparatively 
small quantities of opium are sufficient to remove or at any rate to 
dull pain, but after repeated doses the quantity has to be incr 
owing to tolerance being attained. Some forms of pain are relieved 
by the members of the antipyrine series, but these are less certain 
and more limited in their action than morphine. On the other hand 
the antipyretics often relieve pain without inducing sleep, and in this 
possess a great advantage over opium in the treatment of headache, 
neuralgia and similar conditions. 

Sleeplessness. — Opium was formerly the only drug used to induce 
sleep, but since the discovery of chloral and its congeners it is used 
less frequently. These fail entirely to replace it, however, where the 
sleeplessness is due to pain, while, on the other hand, they are more 
efficacious in some conditions of excitement. Xot infrequently opium 
and chloral are prescribed together for this purpose, and the combi- 
nation acts more efficiently than either of the drugs alone. Each is, 
of course, prescribed in considerably smaller amount than if adminis- 
tered separately. Opium is less efficient than chloral when there is 
apparently an increased activity of the motor functions of the brain, as 
in wild delirium and mania, and sometimes seems to increase the excite- 
ment even, but this general statement is subject to numerous excep- 
tions, and morphine is still largely used in many such disorders. In 
the true convulsive diseases, such as tetanus, epilepsy and chorea, 
chloral is preferable. The beneficial effect of morphine in many acute 
febrile conditions is undeniable, and, as in the case of alcohol, is due 
to its lessening the pain and discomfort of the patient and inducing 
rest. A good deal of difference of opinion exists as to the advisability 
of administering opium or morphine in these conditions, and there is 
no question that the routine treatment of fever by narcotics is to be 
deprecated ; but on the other hand, the restlessness and discomfort 
may in itself aggravate the disease, and morphine is distinctly indicated 
under these circumstances. 

The preparations chiefly used to relieve pain and promote sleep are 
the extracts, laudanum, opium pill, or compound soap pill, and the 
morphine salts and their solutions. The latter may, of course, be ad- 
ministered hypodermically. 

In Respiratory Disorders, opium and morphine are largely used for 
their effects on the centre. Where it is desirable to lessen its irrita- 
bility, as for example in excessive cough and dyspnoea, opium may 
be indicated. On the other hand, when there is a profuse expectora- 
tion, the irritability of the centre cannot be lowered without danger, 
and opium is contraindicated. Opium gives relief in cases of asthma, 
but there is always danger of inducing the habit. 

Opium is often combined with expectorants in the treatment of 
Sough, and a large number of suitable preparations are provided in 
the pharmacopoeias, sueh as paregoric, Dover's powder and other prepa- 
rations containing ipecacuanha, liquorice mixture, the compound mor- 
phine powder (U. S. P.), the ammoniated tincture, the compound 



224 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

tincture of chloroform and morphine, the pills of ipecacuanha and 
squill (B. P.), the lozenges and the codeine preparations. Codeine is 
often preferred to morphine in these cases, because it reduces the ex- 
citability of the respiratory centre with less marked cerebral depression. 
This is also true of the new artificial alkaloids, heroine and dionine, 
which have enjoyed some popular reputation in late years. Impartial 
investigators of these drugs have generally failed to obtain better 
results from them than from codeine and morphine, and further inves- 
tigation is required before they can be recommended as superior to the 
older and unpatented alkaloids. 

In Peritonitis and Intestinal Disorders, opium is indicated doubly ; 
first, for its general action in allaying pain and restlessness ; and secondly, 
for its special action in lessening the movement of the intestine. Opium 
is preferable to morphine for these purposes because it lies longer in 
the bowel, and therefore evolves a stronger action there than on the rest 
of the economy. In colic, especially lead colic, it often relieves the 
pain without increasing the constipation and seems to allay the spasm 
of the bowel without stopping entirely its peristalsis. In diarrhoea 
opium may be given to check the excessive peristalsis, though in the 
severer forms of dysentery it generally fails to have this effect, and in 
septic purging is rather to be avoided. In perforation and hemor- 
rhage from the bowel, opium is the most efficient of all remedies, as it 
allows adhesions or clots to be formed by checking movements of the 
intestine, which would provoke further leakage. 

The B. P. offers a number of preparations specially designed for 
use in intestinal disorders and especially in diarrhoea, such as the com- 
pound kino powder, the compound chalk powder, the lead and opium 
pill, and the compound lead suppository and morphine suppository. 
Instead of these the tincture, extract or other simple preparation may, 
of course, be used. 

In Haemorrhage, where the bleeding point cannot be reached, opium 
or morphine is most valuable. This is not from any direct effect on 
the vessels or blood, but because it allays the restlessness which follows 
the loss of large quantities of blood and thus allows the blood to clot 
in the ruptured vessel. The same preparations are suitable here as for 
pain. 

In Vomiting morphine is sometimes used in small quantities, but it 
seems doubtful whether with any benefit. 

Opium has been used instead of quinine in Malaria, and though it 
cannot be said to replace the latter, has a distinct effect in some cases 
apparently. Of course, symptoms may arise in malaria as in other 
diseases in which opium is specially indicated, but apart from this, 
cases of malaria of old standing seem to be benefited by opium with or 
without quinine. According to Roberts, the action is due to narcotine 
and not to morphine. 

Opium or morphine has sometimes been used- in Diabetes with good 
effects ; for though the glycosuria seldom disappears under its use, it is 
lessened in some cases. Codeine has been advised instead of morphine 



OPIUM SERIES. 225 

in this disorder, as it is less likely to cause constipation and gastric dis- 
turbance. According to many authorities the only effect of these nar- 
cotics in diabetes is to allay the tormenting thirst, while others suppose 
that they retard the formation of sugar from glycogen in the liver. 

Lastly, opium is used as a Diaphoretic, and for this purpose it is gen- 
erally combined with ipecacuanha and prescribed as Dover's powder. 
Although in itself it has little or no diaphoretic action, opium may 
augment the effects of ipecacuanha through dilating the skin vessels. 
Opium and its alkaloids have no effect applied to the skin, and the 
plasters, ointments and other similar preparations are quite superfluous. 

Codeine is much less often used than morphine in therapeutics. It 
is of comparatively little value in allaying pain or excitement, but 
has been found of benefit in the sleeplessness of melancholia. It is 
used not infrequently as a sedative in cough, and, as has been stated, 
in diabetes. There seems less liability to the formation of the codeine 
habit, and it has been suggested as a substitute for morphine in mor- 
phinomania, but has not proved efficient in this condition. 

Opium and morphine are contraindicated in very young children, 
in whom even minute quantities often produce the most alarming 
symptoms of poisoning. Even one drop of laudanum is said to have 
been fatal to a child under one year of age. In great weakness, 
especially in cases where the respiration is barely sufficient to aerate 
the blood, or where profuse expectoration is present, morphine has to 
be administered with the greatest care. In cerebral congestion and 
meningitis the opiates are generally contraindicated. It must be re- 
membered also that both opium and morphine are liable to disturb the 
digestion and to cause nausea and want of appetite, and that these may 
prevent their use in cases in which they would otherwise be suitable. 
In some persons opium invariably causes nausea and vomiting, either 
soon after its administration or while its effects are passing off. For 
this idiosyncrasy morphine may be substituted for opium, although this 
is often equally nauseating, or chloral and bromides may be prescribed 
with opium to prevent the unpleasant after-effects. Not infrequently, 
however, opium has to be avoided entirely. In all chronic painful 
diseases opium or morphine has to be given guardedly, on account of 
the risk of the formation of the opium habit ; the patient ought to be 
kept in ignorance of the drug used as far as possible, and it should be 
alternated with others. Of course, in cases of incurable, hopeless dis- 
ease, where life can only last a comparatively short time and is attended 
by severe suffering, this objection does not hold, and it may be neces- 
sary to administer morphine without stint and in ever-incrca-in^ 
quantity. 

Morphine and opium are often said to be contraindicated in Bright's 
disease of the kidney. This seems to be due to the belief that mor- 
phine is excreted in the urine, which has now been shown to be erro- 
neous. There seems no reason to believe that morphine is harmful in 
these conditions, and in some forms of uraemia it has even been of 
considerable benefit. 
15 



226 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

Acute Poisoning with morphine or opium is the commonest of all 
forms of intoxication, with the exception of the alcoholic. It is often 
difficult to diagnose from other forms of unconsciousness, but the ex- 
treme contraction of the pupils give a clue, as a general rule, and if 
opium has been used, the breath often has the characteristic odor. 

The treatment is immediate evacuation of the stomach, whether the 
drug has been taken by the mouth or not, as even when injected hypo- 
dermically it is excreted into the stomach and may be reabsorbed. 
Emetics may be employed for this purpose, but often fail of effect 
owing to the depression of the medullary centres, so that where possible 
a stomach tube ought to be used in preference. The stomach should 
be thoroughly washed out at intervals, in order to remove every 
trace of the drug as it is excreted. As the respiration begins to fail, 
it is to be encouraged by irritation of the skin, either by dashing cold 
water on it, by the electric current, or by flipping it with towels. 
The violent flagellation formerly advocated with the view of en- 
couraging the respiration, served also usually to exhaust the nervous 
energy both of patient and attendant. When these means fail to keep 
up the natural breathing, it is necessary to resort to artificial respira- 
tion, either electrical or mechanical, and this ought to be continued as 
long as the heart continues to beat. Enormous doses of morphine and 
opium have been recovered from under this treatment. Numerous drugs 
have been advocated in acute morphine poisoning, and of these caffeine 
administered either hypodermically or in the form of strong coffee 
by the stomach seems the most satisfactory. A long controversy has 
been carried on as to whether atropine is to be considered an antidote 
to morphine and used in these cases. It is a stimulant to the medullary 
centres, and may, therefore, be used in small quantities ; but large quan- 
tities, such as have been advised by some authorities, are undoubtedly 
harmful, as atropine itself paralyzes the respiration when given in 
sufficient amount. Bashford states that the best effects are to be ex- 
pected from about 1.5 mg. (^ gr.) of atropine and that more than this 
increases the danger of respiratory failure. In discussing this ques- 
tion too great weight has been laid on the results of animal experi- 
ment, which is not convincing in this case, as the effects of morphine 
are so different in man. Caffeine seems certainly more indicated than 
atropine, for it is scarcely possible to paralyze the respiratory centre 
with the former, which stimulates it equally strongly. Alcohol has 
been advised also, and as far as its local action is concerned, it may 
increase the respiration, but its direct action on the respiratory centre 
is similar to that of opium. Of late years permanganate of potash has 
been advised in case of morphine poisoning, because the poison is oxi- 
dized by it. A certain amount of poison in the stomach may be de- 
stroyed in this way, but the portion absorbed is unaffected by the per- 
manganate, and the method is less efficacious than the prompt and 
repeated use of the stomach tube. The hypodermic injection of per- 
manganate is, of course, entirely useless. 

Chronic Opium or Morphine Poisoning is a not infrequent condition, 



OPIUM SERIES. 227 

and, unfortunately, seems to be increasing rapidly. Among Eastern 
nations, especially in China and India, opium is smoked, and some of 
the morphine is carried over in the smoke and absorbed from the res- 
piratory tract. This habit is rare in European peoples, among whom 
the drug is taken by the mouth, generally in the form of laudanum or 
of pills, or is injected hypodermically as morphine hydrochlorate or 
sulphate. Of the three methods the first seems to be the least harmful, 
for in some parts of China the majority of the adult population seem- 
to indulge in it without the serious results which are met with in the 
Western opium-eaters and morphinomaniacs. This result may be due 
in part to race, or to the fact that the opium-smoker never attains to 
the immense doses taken daily in the cases of the habit met with in 
Europe and America. In the beginning the quantity used is small, 
but as tolerance is attained, ever larger quantities are required to pro- 
duce any effect, until, as De Quincy states in his " Confessions of an 
Opium-eater," 8000 drops of laudanum may be required to stay the 
craving. The effects are generally described as stimulant, but it seems 
possible that they consist rather in depression of the sensibility, by 
which the unfortunate patient becomes unconscious of the miseries of 
his condition, and may accordingly be able to perform his duties and 
maintain appearances better than when deprived of the poison. The 
symptoms of the opium habit are exceedingly indefinite, and the diag- 
nosis is often almost impossible. The statements of the patient ought 
not to be taken into consideration, because these unfortunates seem to 
have lost all idea of honor and truthfulness. As a general rule they 
are nervous, weak in character and wanting in energy, and utterly 
unfit for work unless when supplied with the drug. The pupils are 
often contracted, the heart sometimes irregular, and tremors and un- 
steadiness in walking may be apparent. The appetite is bad and a 
considerable loss in weight occurs, and the movements of the bowels 
are irregular, constipation alternating with diarrhoea. Eventually 
melancholia and dementia may follow the prolonged use of opium, 
and especially of morphine. Some continue the habit for many years, 
however, and it would seem with comparative immunity. If mor- 
phine is injected habitually, evidence may be obtained from the small 
needle marks on the front of the body, which often give rise to mul- 
tiple abscesses of small size from carelessness in the disinfection of the 
syringe. When other evidence fails, it may be necessary to give a 
moderate dose disguised in some unusual way and to observe if it in- 
duces sleep ; in habitual users the ordinary dose will have little or no 
effect. 

The treatment of chronic morphine poisoning is not very promising. 
The will and self-control would seem completely paralyzed in many 
oases, and although the patient wishes to be freed from his enemy, he 
seems utterly unable to withstand the craving. The only means of 
treatment which promises success in most cases is the strict regime of 
an asylum or retreat, where the patient is kept under constant super- 
vision. The immediate removal of the drug often produces such in- 



228 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

tense misery and depression as to seem actually dangerous ; but the 
withdrawal ought not to be too gradual, and ought to be complete after 
two or three weeks at the most. The patient has to be watched care- 
fully for long after he has apparently recovered, as relapses are ex- 
ceedingly common. 

The morphine habit has often been combated by the substitution of 
other drugs, such as cocaine, but the result generally has been that a 
new and even more dangerous habit has been substituted for, or often 
merely grafted on, the original. Numerous drugs have been proposed 
for the cure of morphinomania, but none of them seems to have the 
slightest effect. 

Bibliography. 

The literature of opium is so immense that only a few of the more important phar- 
macological papers can be mentioned here. 

CI. Bernard. Lecons sur les Anaesthesiques et sur 1' asphyxia. Paris, 1875. 

Harley. Old Vegetable Neurotics. London, 1869. 

Kolliker. Virchow's Archiv, x., p. 244. 

Hitzig. Untersuchungen iiber das Gehirn. Berlin, 1874. 

Gscheidlen. Untersuchungen aus dem physiologischen Laboratorium zu Wurzburg, 
ii., p. 1. 

Baxt. Arch. f. Anat. und Phys., 1869, p. 112. 

Filehne. Arch. f. exp. Path. u. Pharm., x., p. 442; xi., p. 45. Pfliiger's Arch., 
lxii., p. 201. 

Loewij. Pfliiger's Archiv, xlvii., p. 601. 

Araki. Ztschr. f. phys. Chem., xix., p. 422. 

Salvioli. Arch. f. Anat. und Phys., 1880, Supplement, p. 95. 

Bubnoff u. Heidenhain. Pfliiger's Arch., xxvi., p. 137. 

v. Schroeder. Arch. f. exp. Path. u. Pharm., xvii., p. 96. 

Witkowski. Arch. f. exp. Path. u. Pharm., vii., p. 247. 

Pohl. Arch. f. exp. Path. u. Pharm., xxxiw, p. 87. 

Alt. Berl. klin. Woch., 1889, p. 560. 

Levison. Diss. Bonn, 1894. Berl. klin. Woch., 1894, p. 891. 

Brunton u. Cash. Beitriige zur Physiologie, C. Ludwig gewidmet, 1887, p. 149. 

Stochnann and Dott. Proc. Row Soc. Edinburgh, 1890. British Medical Journal, 
1890, ii., p. 189, and 1891, i., p. 157. 

Engel. Arch. f. exp. Path. u. Pharm., xxvii., p. 419. (Protopine. ) 

Rheiner. Therap. Monatsch., 1889, p. 393. (Codeine.) 

Dreser. Ibid., 1898, p. 509. 

Stursberg. Arch, de Pharmacodyn., iw, p. 325. 

Winternitz. Pfliiger's Arch., lxxx., p. 344. 

Marshall. Med. Chronicle, April, 1901. 

Riegel. Ztschr. f. klin. Med., xl., p. 347. 

Hirsch. Centralbl. f. inn. Med., 1901. 

Bashford. Arch, internat. de Pharmacodyn., viii., p. 311. 

Faust. Arch. f. exp. Path. u. Pharm., xliw, p. 217. 

Minor Drugs of the Opium Series. 

In some other members of the poppy family (Papaveracese), alkaloids are 
found which bear a close resemblance to those of opium. There are Cheli- 
donine, a- ? /3- eucidy-BIomochelidonine, Chelerythrine and Sanguinarine ; Protopine 
is also found in a number of other papaveracese. These alkaloids are met 
with in very small quantities in various plants, of which Sanguinaria Cana- 
densis (Bloodroot) and Chelidonium majus (Celandine) are the best known. 

Chelidonine and a-homochelidonine resemble morphine in their effects on the 
central nervous system, but have even less stimulant effect. In the frog no 
secondary increase in the reflex irritability is produced, but in some mam- 
mals a slight stimulation of the spinal cord may be caused. They have the 
same effect as protopine and cryptopine on the muscles and heart, and like 



OPIUM SERIES. 229 

them produce insensibility of the skin and cornea when applied locally 
through paralyzing the terminations of the sensory nerves. The heart is 
slowed, partly owing to stimulation of the inhibitory centres in the medulla, 
and partly through direct action on the cardiac muscle. 

Sanguinarine has very little depressant action, but causes tetanus and wild 
excitement, so that as far as its action on the central nervous system is con- 
cerned, it deserves a place between codeine and thebaine of the morphine 
series. It possesses the same muscular action as protopine, however, and 
the heart is slowed through direct affection of the muscle. Sanguinarine 
paralyzes the peripheral sensory endings when applied locally, but this 
paralysis is preceded by a stage of irritation. It causes violent peristalsis of 
the bowel, and increases the secretion of saliva. 

p-homochelidonine resembles protopine and cryptopine closely in its effects, 
causing the same stimulation of the lower parts of the brain with very slight 
effects on the intellectual powers, slowing the heart through its muscular 
action and paralyzing the sensory terminations. 

Chelerythrine paralyzes the central nervous system without any prelimi- 
nary increase in the reflex irritability, possesses the muscular action of pro- 
topine and cryptopine, and first irritates and then paralyzes the sensory 
terminations. 

None of these alkaloids have been used in therapeutics, and there would 
seem to be no indication for them that is not as well met by opium or 
morphine. None of the plants containing them have been used to any great 
extent, although Sanguinaria Canadensis was formerly occasionally pre- 
scribed as a nauseating expectorant and emetic. The ' ' sanguinarine ' ' of 
commerce is generally a mixture of the alkaloids with other constituents, 
and, like the other preparations of the plant, might well be dispensed with. 

U. S. P. Preparations. 

Sanguinaria, the rhizome of Sanguinaria Canadensis, bloodroot, collected 
in autumn. 

Tinctura Sanguinarias, 1-2 c.c. (15-30 mins.). 

Extractum Sanguinarise Fluidum, 0.1-0.5 c.c. (2-8 mins.). 

Chelidonium, celandine, the entire plant of Chelidonium majus. 

Bibliography. 

H. Meyer. Arch. f. exp. Path. u. Pharm., xxix., p. 397. 
Schmidt. Arch, der Pharmacie, ccxxxix., p. 393. 

Anhalonium. — A number of alkaloids, some resembling morphine, others 
strychnine in their effects on animals, have recently been isolated from dif- 
ferent members of the Anhalonium genus (Fam. Cactacese). In Mexico, and 
along the southern boundary of the United States, where those plants are 
indigenous, some of them are used as narcotics in the religious rites of the 
Indians and are known as Pellote, Peyotl, or Muscale or Mezcal Buttons. 
The symptoms arise for the most part from the cerebrum and differ from those 
of opium and cannabis indica in the frequency with which color visions are 
induced, these consisting in constantly shifting flashes of brilliant colors. 
Mezcal eating is not followed by merriment as in cannabis nor by sleep like 
morphine but depression of some functions is indicated by the imperfect co- 
ordination of the movements, the retarded perception and the errors in the 
estimation of time. The exaltation seems to be caused for the most part by 
one of the alkaloids, mezcaline. Very large doses have induced unpleasant 
symptoms through depression of the respiration. Anhalonium and pellotine, 
one of its alkaloids, have been used as narcotics in a few cases of insomnia. 

Lewin. Arch. f. exp. Path. u. Pharm., xxiv., p. 401 ; xxxiv., p. 374 

Heffter. Ibid., xxxiv., p. 65 ; xl., p. 385. 

Prentiss and Morgan. Med. Kecord, 1896, Aug. 22. 

Dixon. Journ. of Physiol., xxv., p. 69. 



230 ORGANIC DRUGS ACTING AFTER ABSORPTION . 

IV. HYDRASTINE AND HYDRASTININE. 

Another alkaloid which is closely related to those of opium chem- 
ically and pharmacologically, is Hydrastine, which occurs in the 
Hydrastis Canadensis (Golden Seal) along with Berberine and Cana- 
dine. 

Hydrastine (C 21 H 21 N0 6 ), when exposed to oxidizing agents such as 
potassium permanganate, is decomposed into opianic acid and Hydras- 
tinine (C n H 13 N0 3 ), another alkaloid. Narcotine (C 22 H 23 NO), the 
opium alkaloid, undergoes a similar decomposition into opianic acid 
and Cotamine (C 12 H 15 N0 4 ). Hydrastine and narcotine differ only in a 
hydrogen atom of the former being substituted by — OCH 3 in the latter, 
and a similar relation exists between hydrastinine and cotarnine. All 
four are derivatives of isoquinoline. The action of hydrastis is simi- 
lar to that of hydrastine, the berberine and canadine having little ef- 
fect ; the latter is as poisonous as hydrastine, but is present only in 
very small quantities in the plant. 

Action. — Hydrastine causes in frogs an increase in the reflex irrita- 
bility and eventually tetanus exactly resembling that produced by 
strychnine, and like it terminating finally in paralysis. Unlike strych- 
nine, however, it weakens and eventually destroys the muscles in 
the same way as the alkaloids of sanguinaria. The heart is rendered 
slow and weak, partly by the central stimulation of the inhibitory ap- 
paratus and partly by direct action on the muscle fibres. 

In mammals, the pulse is slowed by comparatively small quantities, 
while somewhat larger doses cause general feebleness, tremor, dyspnoea, 
and incoordination in the movements. Very large quantities elicit 
clonic and then tonic convulsions and tetanus, during which the respira- 
tion ceases. The pulse is slowed at first from stimulation of the vagus 
centre, is afterwards quickened from its paralysis, and still later be- 
comes slow again from direct action on the cardiac muscle. The 
blood-pressure rises from constriction of the arterioles but after- 
wards falls, partly from their dilatation and partly from the weakness 
of the heart ; the constriction of the arterioles is due to stimulation of 
the vaso-motor centre in the medulla. Several authors have asserted 
that the injection of hydrastine solution is followed by rhythmic con- 
tractions of the uterus similar to those observed during labor, but this 
has been denied by others, and cannot be said to have been satisfac- 
torily established either by experiment or by clinical experience. 
Another statement which is frequently met, is that hydrastis and 
hydrastine increase the secretion of the bile, but this is founded upon 
very imperfect experiments and is in all probability erroneous. Hy- 
drastine has no local anaesthetic action. 

Hydrastine then stimulates first the centres of the medulla oblongata, 
and produces slowing of the pulse, an increased arterial tension and 
accelerated respiration. Larger quantities stimulate further the spinal 
cord and eventually paralyze both medulla and cord. In addition 
to this central action, hydrastine weakens and paralyzes muscle, this 



HYDRASTINE AND HYDRASTININE. 231 

being confined to the heart in warm-blooded animals, but extending 
to the ordinary striated muscle of the frog. 

These effects would appear to give hydrastine a position near that of 
thebaine, though it differs from most of the opium alkaloids in 
seeming to act more strongly on the medulla than elsewhere in the 
central nervous system. Its action on the heart and muscle is analo- 
gous to that of several of the opium alkaloids. Hydrastine is excreted 
as such in the urine, and does not form hydrastinine in the organism 
as might have been surmised from its behavior towards oxidizing sub- 
stances. When it is administered for some time, a cumulative action 
is said to be developed. 

Canadine in small quantities produces depression and drowsiness followed 
by complete recovery without further symptoms. In larger quantities v. 
Bunge found that it caused a short stage of excitement, which was followed 
by depression and paralysis of the central nervous system. It has little or 
no effects on the mammalian circulation when administered in ordinary 
doses, but very large quantities cause weakness and arhythmia of the heart. 
Its injection is followed by violent peristalsis of the intestine and diarrhoea. 
Canadine is present in only very small quantity in the Golden Seal and has 
apparently little importance in therapeutics. 

Hydrastinine, an artificial alkaloid formed from hydrastine, has of 
late years attacted a certain amount of attention from its alleged power 
of arresting hemorrhage. It seems to differ from hydrastine in caus- 
ing no marked disturbance of the centres of motion and feeling save 
in enormous doses, which paralyze the nervous system, and, in the frog, 
the terminations of the motor nerves in muscle (Santesson). On the 
other hand, its action on the medulla oblongata resembles that of the 
parent substance. The heart is slowed somewhat by small doses, ap- 
parently from stimulation of the vagus centre, and the arterial tension 
rises further than after hydrastine. Unlike the latter, however, hy- 
drastinine causes a very prolonged augmentation of the blood-pressure, 
because it does not tend to depress the heart to the same extent as hy- 
drastine. In fact, several authors believe that it increases the effi- 
ciency of the heart movements from action on the muscle, although the 
pulse may be somewhat slowed by stimulation of the inhibitory centre. 
After very large quantities, the pulse is often extremely rapid from 
paralysis of the inhibitory centre. 

The cause of the increased arterial tension is still undecided. There 
seems to be undoubted stimulation of the vaso-motor centre, but ac- 
cording to some writers, the peripheral vessels are contracted by direct 
action on the walls as well. This statement seems open to question, 
however, none of the experiments on which it is founded being alto- 
gether satisfactory ; thus, while Falk found well marked contraction 
of the abdominal, and especially of the renal vessels, v. Bunge denies 
that the renal vessels are constricted. It has been repeatedly stated 
that hydrastinine produces rhythmical contraction of the uterus, and 
even abortion in animals, but this does not seem to be correct. It ap- 
pears to have no direct action on the muscle of this organ, but its ves- 



232 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

sels undergo constriction like those of the rest of the body, and this 
may stop haemorrhage and at the same time cause asphyxia of the 
foetus and abortion. It must be stated, however, that several writers 
on hydrastinine hold that it causes contraction of the uterus through 
action on the muscle, and the question deserves further investigation. 
Archangelsky states that a 10 per cent, solution of hydrastinine ap- 
plied locally causes dilatation of the pupil, which reaches its maximum 
in 2-3 hours, and lasts for 12-15 hours. 

Preparations. 

Hydrastis (U. S. P.), Hydrastis Rhizoma (B. P.), the rhizome and roots 
of Hydrastis Canadensis, Golden Seal. 

Extraction Hydrastis Fluidum (U. S. P.), 1-4 c.c. (15-60 mins.). 

Extraction Hydrastis Liquidum (B. P.), 5-15 mins. 

Glyceritum Hydrastis (U. S. P.), 1-4 c.c. (15-60 mins.). 

Tinctura Hydrastis (U. S. P., B. P.), 1-4 c.c. (15-60 mins.). 

Hydrastinine Hydrochloras (U. S. P.), 0.03-0.1 G. (£-2 grs.), given in so- 
lution hypodermically or by the mouth, or in pills or tablets. 

Therapeutic Uses. — Hydrastis has been used as a stomachic bitter 
and the large quantity of berberine contained in it would seem to give 
it a place along with the simple bitters. It has also been credited with 
some obscure action on the mucous membranes when locally applied, 
through which it is said to benefit many forms of catarrhal inflamma- 
tion. For this purpose the glycerite may be used. Besides various 
conditions in which its use was attended by doubtful success, it has 
been used in haemorrhage from the uterus ; but for this purpose, 
hydrastinine ought to be preferred, as it causes a much greater con- 
striction of the peripheral vessels than hydrastine, and acts less on 
the heart. The conditions in which it is indicated seem to be moder- 
ate haemorrhage, for which no contraction of the uterine walls is re- 
quired ; for example, hydrastinine is of value in excessive menstrual 
flow, while in post-partum haemorrhage it seems to have little effect, 
because here the haemorrhage is to be met rather by inducing contrac- 
tion of the uterine walls by the use of ergot than by constricting the 
vessels, There seems no reason why hydrastinine should not be used 
in other forms of haemorrhage, for it does not act more on the uterine 
vessels than on others throughout the body. 

Hydrastinine has been found to lessen somewhat the irritability of 
the motor areas of the brain, and its use has, therefore, been suggested 
in epilepsy. 

Cotarnine has been introduced under the name of Stypticine as a substitute 
for hydrastinine in uterine haemorrhage. Dose, 0.02-0.03 G. (i~J gr.). It 
resembles hydrastinine in its general action and has received some recom- 
mendation at the hands of gynecologists. 

Bibliography. 

P. Maffori. Arch. f. exp. Path. u. Pharm., xxvii., p. 161. Arch. Ital. de Biol., 
xxviii., p. 191. 

E. Folk. Virchow's Arch., cxix , p. 399 ; cxlii., p. 360. 



CANNABIS INJDICA. 233 

Cerna. Therap. Gaz., 1891, pp. 289, 361. 

K. v. Bunge. Arbeiten a. d. pharmakolog. Institut. Dorpat, xi. and xii., p. 119. 
'Fellner. Centralbl. f. Physiol., xi., p. 374. 
! Santesson. Skandin. Arch. f. Physiologie, vi., p. 308. 
Ronsse. Arch, de Pharmacodynam., iv., p. 207 ; v., p. 21. 
Philipps and Pembrey. Brit. Med. Jour. 1898, ii., p. 1052. 

V. CANNABIS INDICA. 

The hemp plant possesses no pharmacological interest when grown 
in temperate regions, but when cultivated in warm climates as in 
India, Egypt or the southern United States, it develops products which 
induce marked derangements of the central nervous system. The 
Indian plant was formerly supposed to be a distinct species, but differs 
so little from the European form that botanists now consider them 
merely varieties. The old name of Cannabis Indica has, however, 
been retained in medicine. Its introduction into Western medicine 
dates only from the beginning of last century, but it has been used as 
an intoxicant in Asiatic countries and in Africa since unknown time, 
and under the names of Hashish, Bhang, Ganja, C haras or Churrus, 
is habitually indulged in by some one or two hundred millions of 
mankind. Some of the preparations are smoked either alone or mixed 
with tobacco ; others form an intoxicating drink, while in others it is 
mixed with sugar or honey and taken as a confection. 

A large number of investigators have attempted to isolate the ac- 
tive principle of Indian hemp, and its virtues have been attributed in 
turn to a resin, a glucoside, and one or more alkaloids, each investi- 
gator invariably failing to confirm the statement of his predecessors. 
The latest examination, by Wood, Spiney and Easterfield, resulted in 
the discovery of a number of terpenes and of a red oil or resin boiling 
at a high temperature, which they term Cannabinol, and which was 
found by Marshall to induce the typical effects of cannabis indica in 
man and in animals. Its characters and true nature can be discovered 
only by further investigation, but it seems likely that it will prove 
nearly related to the active principles of some of the volatile oils. The 
pharmacological action of cannabis indica presents so many features in 
common with that of opium and in particular with that of anhalonium 
that it may be assigned a place near them. 

Symptoms. — The effects of cannabis indica are chiefly due to the 
changes in the central nervous system, in which it induces a mixture 
of depression and stimulation similar to that seen occasionally under 
morphine. Its action is much less constant, however, and seems to 
depend very largely on the disposition and intellectual activity of the 
individual. The preparations used also vary considerably in strength, 
and the activity of even the crude drug seems to depend very largely 
on the climate and season in which it is grown, so that great discrep- 
ancies occur in the accounts of its effects. Soon after its administra- 
tion, the patient passes into a dreamy, semiconscious 3tate, in which the 
judgment seems to be lost, while the imagination is un trammeled by 
its usual restraints. The dreams assume the vividness of visions, are 



234 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

of boundless extravagance, and, of course, vary with the character and 
pursuits of the individual. In the eastern races they seem generally 
to partake of an amorous nature. The true believer sees the gardens 
of paradise and finds himself surrounded by troops of houris of un- 
speakable beauty, while the less imaginative European finds himself un- 
accountably happy and feels constrained to active movement, often of a 
purposeless and even absurd character. Ideas flash through the mind 
without apparent continuity, and all measurement of time and space 
is lost. True hallucinations may appear, but are often absent, the 
chief features of the action being merriment, comfort, well-being and 
self-satisfaction. Often less pleasant thoughts obtrude themselves, 
however, such as the fear of impending death or of some imminent in- 
definite danger. During this period, the consciousness is not entirely 
lost, for the patient often feels that his dreams are unreal, his satisfaction 
unfounded and his movements ridiculous, but he cannot restrain them ; 
he can give a coherent account of his condition when aroused and 
answer questions intelligently. The sensation of pain is lessened or 
entirely absent, and the sense of touch is less acute than normally. 
Later the dreams alternate with periods of complete unconsciousness, 
from which the patient can be aroused easily, and the symptoms 
eventually pass into tranquil sleep, from which he awakes refreshed, 
and, as a rule, without any feeling of depression or nausea. In the 
majority of cases the preliminary stage of exaltation is very short or 
entirely absent in Europeans, the first effects of the drug often being 
heaviness, drowsiness, noises in the ears and numbness of the extrem- 
ities, which pass into deep sleep. According to Dixon the drug is 
much more exhilarating when inhaled than when sw r allowed, and this 
may account for some of the variations in its action. In some cases, 
acute mania and convulsive attacks have been developed, and among 
the natives of India catalepsy occasionally occurs. 

In animals, the effects of cannabis indica seem to resemble those in 
man and present the same marked variations ; a stage of exaltation with 
increased movement is sometimes present and is followed by depres- 
sion, lassitude and sleep. The reflex excitability is first increased and 
then diminished in frogs. Vomiting is often induced in dogs and cats, 
but cannabis indica differs from opium in producing no disturbance of 
the digestion and no constipation. The heart is generally accelerated 
in man, when the drug is inhaled ; the intravenous injection in animals 
slows the pulse partly through inhibitory stimulation and partly 
through direct action on the heart muscle. This action on the heart is 
stated by Dixon to be the cause of death after poisonous quantities, for 
he found the respiration persist for some seconds after standstill of the 
heart. The pupil is generally somewhat dilated. JNo effects have 
been noted in regard to the glandular secretion, such as might be 
expected if muscarine were present, as has been asserted. 

Death from acute poisoning is extremely rare, and recovery has oc- 
curred after enormous doses. The continued abuse of hashish in the 
East sometimes leads to mania and dementia, but does not cause the 



APOMORPHINE. 235 

same disturbance of nutrition as opium, and the habitual use of small 
quantities, which is almost universal in some eastern peoples, does not 
seem detrimental to them, although among Europeans it might possibly 
be as fatal as that of morphine. 

Preparations. 

Cannabis Indica (IT. S. P., B. P.), Indian hemp, the flowering tops of the 
female plant of Cannabis sativa (hemp), grown in the East Indies. 

Extractum Cannabis Indies (U. S. P., B. P.), 0.02-0.06 G. Q-lgr.). 

Extractum Cannabis Indicse Fluidum (U. S. P.), 0.1-0.3 c.c. (2-5 mins.). 

Tincture Cannabis Indicle (U. S. P., B. P.), 1-2 c.c. (15-30 mins.). 

The preparations vary extremely in strength and many are entirely inert, 
especially when they have been kept some time. The unofficial prepara- 
tions, such as " cannabin tannate," cannabinon, etc., seem to be no more 
reliable than the pharmacopceial ones, and offer no advantages at all com- 
mensurate with their price. 

Therapeutic Uses. — Cannabis indica is used as a hypnotic in cases of 
sleeplessness from nervous exhaustion and, less often, from pain. It is 
not nearly so reliable as opium, and in fact produces sleep in only about 
50 per cent, of the cases, according to some authors. On the other hand, 
it does not disturb the digestion and produces no subsequent nausea 
and depression, and may therefore be employed in some cases in which 
opium is contraindicated. It is of use in some cases of migraine, and 
has been prescribed as a substitute for opium in mental diseases. 

Lactucarium (U. S. P.), the dried juice of Lactuca virosa, the common 
lettuce, is reputed to have some hypnotic properties. It contains neutral 
bitter substances, lactucin and lactucon, and it has been stated recently that 
traces of hyoscy amine and atropine are also present. In any case its action 
is so feeble that half an ounce has been administered to a dog without effect, 
and it seems quite unnecessary to include it in the pharmacopoeia. 

IT. S. P. — Tinctura Lactucarii. 

Syrupus Lactucarii. 

Bibliography of Cannabis Indica. 

Martins. Inaug. Diss. Erlangen, 1855. (Historical.) 
Hare. Therapeutic Gazette, 1887, p. 225. 
Preisendorfer. Deutsch. Arch. f. klin. Med., xxv., p. 49. 
Wood. Proc. Amer. Phil. Soc, 1869, p. 226. 
Fronmiiller. Erlangen, 1869. 

v. Schroff. Lehrb. der Pharmakologie, 1868, p. 499. 

Zuco u. Vignolo. Arch. Ital. de Biol., xxiii., p. 409. Bericht. der Berl. Chem. 
Gesellsch., 1895, iv., p. 558. 

Marshall. Lancet, 1897, i., p. 235. American Medical Journal, 1898, ii., p. 882. 
Dixon. Brit. Med. Journ., 1899, ii., p. 136. 

VI. APOMORPHINE. 

When morphine is acted on by acids and by some other dehydrat- 
ing agents, it loses a molecule of water, and a new alkaloid is formed, 

A po morphine (0 17 H 17 NO 2 ). 

Through this change the action of the original alkaloid is consider- 
ably modified ; apomorphine preserves the stimulant, but loses to a 



236 



ORGANIC DRUGS ACTING AFTER ABSORPTION. 



Fig. 19. 



great degree the depressant action of morphine on the central nervous 
system. This stimulant action extends over the whole central nervous 
system in animals, but is most developed in the " vomiting centre " of 
the medulla oblongata. 

Symptoms. — In man, apomorphine in doses of 5-10 mg. (^~l £ r -) 
induces within 10-15 minutes nausea and vomiting, accompanied by 
the usual attendant phenomena, but with no symptoms which cannot 
be directly included in these. Very often the nausea passes off imme- 
diately after the evacuation of the stomach, but when larger quantities 
have been administered, repeated vomiting and retching may occur. 

Occasionally depression and sleep follow the 
emesis after even small doses. 

The attendant symptoms are profuse saliva- 
tion, increased secretion of the mucous glands 
of the nose, throat and bronchial passages, 
tears and a cold perspiration. A feeling of 
depression and muscular weakness and accel- 
eration of the pulse are also well-known 
symptoms accompanying nausea and vomit- 
ing, and are present after apomorphine. 
These are all to be regarded as sequelae of the 
emetic action, however, and not as due to 
the direct action of the drug on the glands 
and other organs. In a few instances the 
depression and weakness have passed into 
alarming collapse, but no actual fatality is 
recorded from the use of apomorphine. 

In dogs and cats, small quantities elicit 
the same effects as in man, but larger doses 
are followed by symptoms of general nerv- 
ous stimulation. In the herbivora, which 

are incapable of vomiting, these symptoms 

follow the injection of comparatively small 
oriSnspireTbyl S&ffSg quantities and are much more marked. The 
apomorphine The volume in- ra bbit, for example, becomes restless and 

spired in each iy 2 nuns, is meas- .-i i . , . 

ured along the perpendicular, the easilv alarmed; it moves about, climbs up 

time along the horizontal line. i " n n • , i ,, ■ . 

At first about 600 c.c. represents the walls ot its cage and gnaws anything It 

the average amount, but after the 1 rr x l l J 

injection of apomorphine (A) it can reach. Circus movements are developed 
?&J?£I^J%™- m c ^ very often, especially in the dog, the animal 

running unceasingly in a circle and striking 
against obstacles in its path, apparently unconscious of all its surroun- 
dings and overcome by the impulse to continual movement. The res- 
piration is very much accelerated (Fig. 19). After very large quan- 
tities, the movements become less coordinated, and eventually tetanic 
convulsions set in, during which the respiration ceases, while the heart 
continues to beat for some time afterwards. 

In the frog, apomorphine causes a transient stimulation of the cen- 
tral nervous system, followed by depression and paralysis. Larger 




APOMORPHINE. 237 

quantities weaken and paralyze the muscles and the heart through 
direct action on the fibres. The muscular action may also be demon- 
strated on excised muscles, in which the elasticity is lessened, and the 
contractions become weaker and eventually cease entirely. This weak- 
ening in the contraction of the muscles has not been observed in mam- 
mals, and is quite distinct from the feeling of weakness accompanying 
nausea in man, for the latter is certainly of cerebral origin. No emesis 
is induced in frogs, although these animals are not, like the herbivora, 
incapable of vomiting. 

Very small doses of apomorphine may induce the secondary symp- 
toms without actual vomiting. Thus the saliva, perspiration, tears and 
other secretions may be augmented by quantities which are too small 
to act as emetics, though there is no question that these are due to the 
commencing emetic action. 

Apomorphine induces vomiting through changes in the medulla ob- 
longata and not by irritation of the stomach. This is shown by the 
fact that it acts much more quickly and in smaller doses, when it is 
injected hypodermically than when it is swallowed, and also by the fact 
that if the medulla be brushed with apomorphine solution, vomiting 
follows immediately. It is even disputed whether apomorphine has 
any effect on the gastric movements at all, for Batelli states that the 
stomach remains quite passive during vomiting, while Schutz found it 
undergoing antiperistaltic movements towards the cardiac orifice. In 
any case the movements of the stomach play an unimportant part in 
the evacuation of its contents by apomorphine, and all the phenomena 
in man are to be ascribed to medullary action. 

Apomorphine is said to have some anaesthetic effects on the cornea 
w T hen a solution is dropped upon it. It causes cloudiness and conse- 
quent dimness of sight, however, and has not been used practically 
for this purpose. Apomorphine is not excreted into the stomach 
like morphine, nor has it been found in the mucous membranes of 
the air passages, and it is possible that it is decomposed in the 
tissues. 

The symptoms induced by apomorphine resemble in some degree 
those following morphine in many animals, for here too the first symp- 
tom is vomiting accompanied by signs of excitement, which are, how- 
ever, generally attended by those of depression of some parts of the 
central nervous system. The similarity between the effects of apomor- 
phine and of morphine on the cat, for example, is particularly striking. 
In man, however, the effects are very different, for apomorphine seems 
to have lost all the depressant action of the parent body, although here 
again it must be remembered that morphine occasionally causes vomit- 
ing, so that apomorphine does not depart so far from the type of the 
opium alkaloids as would at first sight appear. 

Apocodeine is formed from codeine in the same way as apomorphine from 
morphine, and according to some observers it acts in the same way as apo- 
morphine when injected in doses of 15-20 mg. (\-\ gr.), but it has been re- 
cently stated that pure apocodeine is not an emetic, but a cerebral depressant. 



238 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

If codeine be heated with hydrochloric acid (B. P.), apomorphine is formed, 
and not apocodeine. 

Preparations. 

Apomorphine Hydrochloras (U. S. P.), 5-10 mg. (fa-\ gr.). 

APOMORPHINiE Hydrochloridum (B. P.), fa-fa gr. 

Injectio Apomorphine Hypodermica (B. P.), 1 per cent., 5-10 mins. 

Apomorphine hydrochlorate is a grayish-white crystalline substance, very 
soluble in water and turning dark green or even black, especially when kept 
long in solution. This change in color does not appear to impair its activity 
appreciably. The doses given above are those for hypodermic use to induce 
vomiting. The same quantity may be given by the mouth as an expectorant. 

Therapeutic Uses. — Apomorphine is used chiefly as an emetic, and 
for some purposes presents several advantages over the older drugs 
employed with this object, inasmuch as it acts more promptly and can 
be administered by the hypodermic needle, while the other emetics 
have to be given by the mouth, which is a serious drawback in cases 
of poisoning. The more important of these older drugs are ipecacu- 
anha, tartar emetic (antimony), ammonium carbonate, the sulphates of 
copper and zinc and alum. 

Vomiting is not now such an important method of treatment as it 
was formerly, and the emetics are less frequently employed to evacuate 
the stomach than other less heroic measures such as the passage of the 
stomach tube. Emesis may be indicated in poisoning, and here apo- 
morphine is especially useful. But in the great majority of cases a 
better method of treatment is repeated washing of the stomach by 
means of the stomach tube, for in narcotic poisoning apomorphine not 
infrequently fails to act owing to the depression of the vomiting centre, 
and in corrosive poisoning a certain amount of danger attends its use, 
as the pressure on the walls of the stomach exerted by the contraction 
of the diaphragm and abdominal muscles may lead to the rupture of 
the weakened walls of the organ. In irritant poisoning, on the other 
hand, the reflex vomiting set up is generally sufficient to empty the 
stomach, and the indications are rather to allay the gastric irritation 
than to increase it by causing violent movements of the abdominal 
walls by apomorphine. Emetics, such as apomorphine, have been used 
occasionally to cause pressure on other abdominal organs, e. g., on the 
gall-bladder in order to dislodge a calculus or plug of mucus in the 
ductus choledochus, but this treatment is not to be advised, owing to 
the risk of rupture of the gall-bladder. Occasionally emetics are used, 
especially in children, to expel bodies from the air passages, as violent 
movements of expiration are produced during emesis. Apomorphine 
is, however, comparatively rarely used for this purpose. In cases of 
choking due to foreign bodies lying in the pharynx, vomiting is often 
beneficial, but the emetics act too slowly to be of benefit here. 

Occasionally vomiting is still induced as a preliminary to treatment 
of various conditions not related to the alimentary canal ; thus before 
commencing the treatment of malaria with quinine, the stomach is 
sometimes emptied by an emetic, while the bowel is evacuated by a purge. 



PRVSSIC ACID. 239 

A second use of emetics is in inflammatory conditions of the res- 
piratory passages ; the object here is to induce an increased secretion 
without producing emesis, and very small quantities are therefore 
used. The special condition in which this class of remedies is of ser- 
vice is bronchial irritation with a sticky mucous secretiou which causes 
cough, but can only be expectorated with difficulty. The indications 
are for a mild and prolonged action such as can be induced by small 
doses of ipecacuanha, antimony and similar bodies, rather than for the 
more transient effects of apomorphine, but the latter has been advised 
by some authorities. 1 

Emesis is contraindicated in all conditions in which a sudden rise of 
blood-pressure may be dangerous, as in atheroma, fatty heart or aneu- 
rism, and where there is any danger of rupture of the abdominal walls 
or organs as in hernia, advanced pregnancy (especially if there be any 
tendency to abortion) gastric ulcer, and generally in impacted gall- 
stone. 

Bibliography. 

Siebert. Inaug. Diss., Dorpat, 1871. Wagner's Archiv. f. Heilkunde, xii., p. 522. 
Quehl. Inaug. Diss., Halle, 1872. 

Hamack. Arch, f. exp. Path. u. Pharm., ii., p. 254; iii., p. 64. Therapeut. 
Monatsh., 1892, p. 270. 

Thumas. Yirchow's Archiv, cxxiii., p. 44. 
MurreU. Brit. Med. Journ., 1891, L, p. 452. 
Guinard, Schmidt's Jahrb., ccxli., p. 130. 

VII. PRUSSIC ACID. 

Prussic or hydrocyanic acid differs entirely from the other acids in 
its pharmacological action, and has therefore to be described apart 
from them. 

The pure acid is scarcely ever seen save in the chemical laboratory, 
and is an extremely dangerous body to handle, as it is very volatile 
and its fumes when inhaled may produce death within a few seconds. 
It is generally met with in a very dilute solution, which is formed by 
the decomposition of one of its salts. 

In nature, prussic acid occurs in the secretion of some of the myria- 
poda, and in the decomposition products of a few glucosides, of which 
Aiiu/gdalin is the best known. Amygdalin is in itself practically in- 
active, but may be decomposed by dilute acids or by a ferment, emul- 
sin, which is generally found associated with it in plants. The prod- 
ucts of its decomposition are prussic acid, benzaldehyde and glucose, 
and the process may be represented by the formula, 

Amygdalin. Prussic Benzaldehyde. Glucose, 

acid. • • * 

C 20 H 27 XO U + 2H 2 = CXH + C 6 H 5 CHO + 2C 6 H 12 6 . 

Both amygdalin and emulsin occur in the bitter almond and in the 
kernels of a number of fruits, such as the apple, cherry, prune, plum 

1 Apomorphine is occasionally mentioned as a hypnotic, but the preliminary vom- 
iting would certainly prevent its use for this purpose unless in quite exceptional con- 
ditions. It is not unlikely that in some instances morphine may be contained in the 
irug and that this may explain this narcotic action. 



240 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

and apricot. In smaller quantities they have been found in the bark 
and leaves of several of these trees and in the laurel (Prunus lauro- 
cerasus). In the sweet almond emulsin occurs, but no amygdalin. 
When bitter almonds are rubbed into a paste with water, prussic acid 
is formed by the action of the feruient on amygdalin, and very large 
quantities of such a paste may give rise to unpleasant symptoms, 
especially in children. A more dangerous substance is the oil of bitter 
almonds, which consists of benzaldehyde and prussic acid in a loose 
combination and in very varying proportions. Several liqueurs are 
distilled from kernels and fruits containing amygdalin, and therefore 
possess a variable percentage of prussic acid. The best known of these 
are Kirschwasser and Maraschino. Laurel water and the preparations 
of Virginian cherry bark contain benzaldehyde and prussic acid, 
although these are in too small quantity to have any poisonous action. 
Prussic acid and its salts have practically the same action, although 
none of the latter are so poisonous as the free acid. Cyanogen, (CN) 2 , 
also resembles prussic acid in its eifects, but is not so active. 

The ferrocyanides and other double cyanides are in most cases harmless 
but other compounds, from which prussic acid is formed in the organism, 
are poisonous. The organic combinations containing the — CN radicle 
form two series, the Nitrites, in which the nitrogen is trivalent (e. g., 
CH 3 — C = N), and the Isonitriles, or Carbylamines, in which the alkyl is at- 
tached to the nitrogen (e. g. , CH 3 — N = C). These compounds are all much 
less poisonous than prussic acid, and the nitriles are said to differ from it in 
their effects, inasmuch as the chief symptoms caused by them arise from 
gastro-intestinal irritation. The isonitriles are more poisonous than the 
nitriles and resemble the acid more closely in their action. Both nitriles 
and isonitriles give rise to the formation of prussic acid in the tissues. 

Symptoms and Action. — Prussic acid first stimulates and then para- 
lyzes the central nervous system in mammals, but it acts on so many 
forms of living matter that it merits the designation of a general proto- 
plasm poison. The fatal dose in man is believed to be about 0.05-0.08 
G. (1-1 J- gr.) of the pure acid, certainly a much larger quantity than is 
fatal in cases of poisoning with some of the alkaloids and glucosides. 
Prussic acid acts much more rapidly than these, however, and has thus 
gained its reputation of being the most dangerous of poisons. 

After very large doses in mammals, there may be practically no 
symptoms ; the animal falls to the ground with a slight convulsive 
movement or a scream, and death follows in a few seconds from simul- 
taneous arrest of the heart and respiration. 

In smaller quantities, prussic acid has a bitter, acrid, burning taste, 
which is accompanied by salivation, and is followed by numbness in the 
mouth and throat. A sensation of warmth in the stomach is followed 
by nausea and vomiting, confusion and headache, dyspnoea, slow pulse, 
and general muscular weakness. The pupils are widely dilated and 
the eyeballs protrude, as generally occurs in asphyxia. Unconscious- 
ness follows, and then violent convulsion, which pass into paralysis 
with involuntary evacuation of the contents of the bladder and bowel, 



PEUSSIC ACID. 



2n 



the respiration becomes extremely slow and eventually ceases, while 
the heart continues to beat for some time afterwards. 

In frogs, no convulsions occur, the symptoms pointing to a paralysis 
of the central nervous system without preliminary stimulation, except 
in that the respiration is somewhat quick and dyspnceic. 

In mammals, the Central Nervous System is first stimulated and then 
paralyzed, but the action seems to be developed more fully in the 
medulla oblongata and lower parts of the brain than in the cerebral 
cortex, for the convulsions resemble those produced by stimulation of 
the hind-brain, although the subsequent paralysis seems to include all 
parts of the central axis. 

The peripheral Nerves and the Muscles are weakened and eventually 
paralyzed when suspended in an atmosphere of the gas, but unless 

Fig. 20. 




Tracing of the movements of the diaphragm (respiration) of the rabbit under a large but not fatal 
dose of cyanide of potash injected intravenously. A-B, normal respiration. Ati? 1 mg. injected ; the 
respiratory movements are much larger. At C recovery. Note the short duration of the stimulation. 

very large quantities are injected, they are not much affected in the 
living animal. When prussic acid in solution is applied locally to the 
Skin, it produces a numbness and partial loss of sensation, but this 
does not follow in general poisoning. The anaesthetic action is well 
seen on brushing the leg of a frog with a weak solution, for no reflex 
can be elicited from subsequent irritation of the limb, although it is 
moved on irritation of other parts of the body, which shows that the 
motor nerves and the spinal cord are still intact. 

The Respiration is rendered quicker and deeper by the injection or 
inhalation of small quantities of prussic acid. During the convulsions 
it is, of course, irregular, and afterwards generally becomes extremely 
slow and deep and then ceases. After very large quantities it may 
cease within a few seconds. These changes are produced by primary 
stimulation and subsequent paralysis of the medullary centre. 
16 



242 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

The Circulation is altered mainly through the action on the central 
nervous system, although prussic acid also acts directly on the heart. 
The stimulation of the inhibitory centre generally slows the pulse, 
but this is accompanied by a very considerable rise in blood-pressure 
from increased activity of the vaso-constrictor centres. This central 
stimulation later passes into paralysis and the blood-pressure falls from 
the depression of the vaso-motor centres, but the heart does not gen- 
erally regain its normal rhythm, because although the inhibitory stimu- 
lation has passed off, the cardiac muscle is now directly affected, and 
its movements therefore remain somewhat slow. During the con- 
vulsions the arterial pressure rises again, but afterwards the progres- 
sive weakening of the heart leads to a slow and imperfect circulation. 
In the frog's heart, prussic acid causes slowing and standstill long be- 
fore the peripheral nerves and muscles are affected. 

If very large quantities be injected intravenously, or inhaled, the 
heart may cease contracting for a few seconds, and then recommence a 
slow and feeble beat, which is very soon arrested again. This is prob- 
ably due to primary action on the inhibitory centre, followed by direct 
paralysis of the heart. 

Batelli has "shown that prussic acid injected hypodermically lessens 
the movements of the stomach. The temperature remains constant or 
rises somewhat after small doses, but falls rapidly when toxic symptoms 
appear. 

Nutrition. — Besides its specific action on the central nervous system, 
prussic acid exercises a depressant action on protoplasm in general, and 
may therefore be called a general protoplasm poison, although some 
of the bacteria are but little affected by it. Both plants and animals 
are retarded in their movements and in their nutritive processes by its 
presence, although they may recover and show no subsequent deteriora- 
tion provided the poison acts only during a short time and in suffi- 
cient dilution. For example, the development of seeds is hindered 
by the presence of prussic acid, but proceeds when it is withdrawn ; 
yeast cells cease their activity, and the insectivorous plant Drosera 
no longer moves its tentacles in the presence of cyanides or prussic acid 
(Darwin). This action in plants has been explained by supposing that 
prussic acid stops by its presence the activity of the ferments which 
play so large a part in the economy of nature. 

The effects of prussic acid on the mammalian tissues have been ex- 
amined by Geppert in a long and careful research. He found that the 
oxygen absorbed by the tissues was much lessened by prussic acid, 
whereas it was to be expected that a convulsive poison, such as that 
under discussion, would cause an increased waste in the tissues and a 
corresponding rise in the oxygen used ; yet during the most powerful 
convulsions after prussic acid, the absorption of oxygen is often dis- 
tinctly lower than in the normal resting animal. After some time the 
consumption of oxygen again increases, although it does not regain the 
normal standard unless complete recovery occurs. The carbonic acid 
actually formed by the tissues falls, owing to the lessened oxidation, 



PRUSSIC ACID. 243 

which, might be due to various causes, for example to the blood being 
less capable of absorbing oxygen than usual. Geppert shows, however, 
that this is not the explanation, but that the tissues are unable to absorb 
the oxygen brought to them by the blood cells ; that, in fact, a change 
occurs in the protoplasm, which retards the normal respiration of the 
cell. The consequence of this is that the oxyhemoglobin of the blood 
is not reduced in the capillaries, so that the venous blood has the same 
bright red color as the arterial. Prussic acid seems to be rapidly 
changed to other products in the tissues, however, provided a lethal 
dose has not been given, and as this process goes on, the protoplasm 
recovers its oxygen-absorbing power, the expired air becomes less rich 
in oxygen and richer in carbonic acid, and the venous blood assumes 
its ordinary dark color. Lactic acid and sugar are found in the blood 
in unusually large quantities during the action of prussic acid ; these 
are invariably present when the oxidation of the tissues is imperfect 
from any cause. 

The changes in the central nervous system are produced by smaller 
quantities and somewhat more rapidly than those in the metabolism, 
and they also last longer. The dilatation of the blood vessels from 
the depression of the vaso-constrictor centre may probably cooperate 
with the lessened absorption of oxygen to produce the bright red color 
of the venous blood, for it stands to reason that a more rapid circula- 
tion through the capillaries must lessen the amount of oxygen given up 
by the blood. 

The diminution in the oxygen absorption by the tissues is of interest 
in relation to the retardation of the ferment action in plants, for Jacquet 
has shown that the tissues oxidize mainly by a ferment action, and there 
would thus seem to be an entire correspondence between the changes 
produced in the metabolism of plants and animals by prussic acid. 

Prussic acid is changed to sulphocyanides in the tissues, and is partly 
excreted in the urine in this form, while part of it undergoes further 
and unknown changes. This combination of prussic acid and sulphur 
bodies, such as the proteids, seems to arise by simple chemical processes, 
without the intervention of living protoplasm being necessary. 

In the animal body prussic acid does not form any combination 
with the haemoglobin of the red blood cells, but in the drawn blood, on 
the other hand, it seems to enter into a curious relation to it, as is 
shown by its reaction to peroxide of hydrogen. If normal blood be 
brought in contact with a solution of the peroxide, it effervesces owing 
to the liberation of oxygen, but the oxyhemoglobin remains unchanged : 
if, however, prussic acid be present no effervescence occurs, but the 
haemoglobin is at once changed to methaemoglobin. Blood to which 
prussic acid has been added retains its red color much longer than 
ordinary blood, which soon assumes a dark venous color from the 
haemoglobin giving up its oxygen. Robert explains both of these 
reactions by supposing that prussic acid destroys some oxidizing sub- 
stance or ferment in the blood. Hoppe-Seyler believes that a loose 
chemical combination is formed by prussic acid and haemoglobin, but 



244 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

that this is very easily decomposed and has the same spectrum as 
oxyhemoglobin. Preyer, on the other hand, described a definite com- 
pound with a distinctive spectrum and possessing quite different re- 
actions to reducing and oxidizing bodies, but his work has not been 
confirmed, and it seems likely that he used some decomposition prod- 
ucts instead of haemoglobin. 

Robert discovered a curious combination of prussic acid and met- 
hsemoglobin, which is formed whenever these two come in contact, 
and is distinguished from ordinary methsemoglobin by possessing a 
bright red color. In cases of cyanide poisoning, the dependent parts of 
the body often present this color, owing to the methsemoglobin which they 
ordinarily contain after death being changed to cyan-methsemoglobin. 

Preparations. 

Acidum Hydrocyanicum Dilutum (TJ. S. P., B. P.), a two per cent, solu- 
tion formed from potassium ferrocyanide or silver cyanide. It is a colorless 
fluid with a characteristic smell and taste, and ought not to be kept long, 
as it is liable to decomposition ; much of that actually used in medicine is 
partially decomposed and therefore under two per cent, in strength. Dose, 
0.1-0.5 c.c. (2-8 mins.). 

Argenti Cyanidum (U. S. P.), is used in medicine only for the formation of 
the dilute hydrocyanic acid. 

A number of other preparations contain prussic acid, generally in very 
variable quantity. Thus in the U. S. P. the preparations of bitter almonds, 
except the expressed oil, contain it, and the volatile oil is, in fact, dangerous 
owing to the large proportion of prussic acid sometimes present. Another 
series of preparations containing it, though only in minute quantities, is 
that of the bark of the wild cherry, Prunus Virginiana. In the British 
Pharmacopoeia the bitter almond, Virginian cherry and the cherry-laurel 
water contain it, but only in harmless quantities. It is also rjresent in the 
tincture of chloroform and morphine, B. P. 

Therapeutic Uses. — The uses of prussic acid at the present day are 
very few. Externally it is applied to itching surfaces to cause numb- 
ing and insensibility of the sensory nerve terminations, but care must 
be taken that the surface is unbroken, or unpleasant and even danger- 
ous symptoms may be induced. It is also used internally in vomiting, 
especially in that occurring in pregnancy, and seems to be beneficial 
occasionally. It was formerly used extensively as a sedative in cough, 
but was generally prescribed along with opium or other narcotics, and 
it seems unlikely that the hydrocyanic acid had any effect. 

In Poisoning with prussic acid or the cyanides, the treatment is that 
of poisoning in general — thorough evacuation of the stomach, warmth 
and general measures against collapse. A number of so-called anti- 
dotes have been proposed, such as atropine, which there is no reason 
to suppose would be of benefit, for it has been found useless in animal 
experiments. The intravenous injection of sodium sulphide and hypo- 
sulphite has been advised on the theory that the comparatively harm- 
less sulphocyanide would be formed, and animals seem to be able 
to survive an otherwise lethal dose when this is done. Peroxide of 
hydrogen has also been suggested, in order to form innocuous oxidation 



CAFFEINE. 245 

products with the prussic acid. Artificial respiration should be 
resorted to when necessary, as the cyanide is comparatively quickly 
rendered inactive, and the recovery is rapid when it once sets in. But 
in many cases life is extinct before medical aid can be called. 

Bibliography. 

Kolliker. Virchow's Archiv, x., p. 272. 
Freyer. Die Blausaure, Bonn, 1868. 

Preyer. Virchow's Archiv, xl., p. 125. PA tiger's Archiv, ii., p. 146. 
Hoppe-Seyler. Medicinisch-chemisch. Untersuch., 1866-1870, p. 133. 
Gaethgens. Ibid., p. 324. 
ZUlessen. Ztsch. f. phys. Chem., xv., p. 398. 
Boehm u. Knie. Arch. f. exp. Path. u. Pharm., ii., p. 129. 
Geppert, Zts. f. klin. Med.', xv., pp. 208 and 307. 

Robert. Ueber Cyanmethajmoglobin und den Nachweis der Blausaure. Stuttgart, 
1891. 

Schar. Naegeli-Kollikersche Festschrift, Zurich, 1891. 

Lang. Arch. f. exp. Path. u. Pharm., xxxiv., p. 247. 

Fascheles. Ibid., p. 281. 

Bunge. Ibid., xii., p. 41. (Cyanogen.) 

Heymanns et Masoin. Arch, de Pharmacodynamique, iii., p. 359. 

VIII. CAFFEINE. 

In a number of plants used in different parts of the world to form 
beverages and condiments, there are found the xanthine compounds, 
Caffeine, TJieobromine and Theophylline, the first two of which have 
been employed in therapeutics of late years, and have, therefore, ac- 
quired a double importance as drugs and as articles of diet. The wide- 
spread use of preparations of these by uncivilized peoples is a curious 
and unexplained fact, especially as they possess neither peculiar taste 
nor odor to guide in the selection of the plants in which they exist. 
Besides, caffeine and its allies in moderate quantities induce no marked 
symptoms, such as follow the use of alcohol, opium or hashish and 
explain their use among widely separated peoples. On the contrary, 
the only effects to be observed are a brightening of the intellectual 
faculties and an increased capacity for mental and physical work. 
Coffee, the use of which is derived from the Arabians, is the berry of 
Coffea Arabica and contains caffeine ; tea, the leaves of Thea Chinensis, 
contains caffeine along with theophylline. 1 Cacao, cocoa or chocolate 
is derived from the seeds of Theobroma cacao, a tree indigenous in 
Brazil and Central America, and contains theobromine. In central 
Africa, the Cola or Kola nut (Sterculia acuminata) is used by the na- 
tives, and contains caffeine with small quantities of theobromine. 
Kolanine, or colanine, which was at one time supposed to be a new body, 
seems to be a compound of tannic acid with these xanthine derivatives. 
In Brazil, Guarana paste is formed from the seeds of Paullinia sorbilis, 
and contains caffeine and theobromine, while in the Argentine Re- 
public, Yerba Mate or Paraguay tea (Ilex Paraguayensis) is used to 
form a beverage which contains a very small quantity of caffeine. 

_ *Tea was formerly supposed to contain theine, but this has proved to be Identical 
with caffeine. 



246 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

Another species of Ilex is met with in Virginia and Carolina under 
the name of Apalache tea or Youpon, and also contains caffeine. 

These three principles, caffeine, theobromine and theophylline, are 
purine derivatives closely related to the xanthine bodies found in the 
urine and tissues of the animals. The members most closely approach- 
ing the vegetable forms are xanthine, paraxanthine and heteroxan thine ; 
the last is a monomethylxanthine, while paraxanthine is a dimethyl- 
xanthine isomeric with theobromine and theophylline, and caffeine is 
trimethylxanthine. The structural formula? may serve to indicate more 
clearly the close relationship of these bodies. 



Xanthine. 


Theobromine. 




NH— C=N \ 

1 II >CH 
CO C— NH/ 

HN— CO 


CH 3 N— C=N \ 
«, kcH> 
NH— CO 








Theophylline. 


Caffeine. 




CH 3 N— C=N \ 

'1 II _ T >CH 
CO 0— NH/ 


CH 3 N— C— N \ 

a 1 ) JUch 3 > 
1 f 

CH 3 N— CO 




CH 3 N— CO 



Action. — These all resemble each other in most points of their 
pharmacological action, although caffeine acts on the central nervous 
system as well as on the kidneys, muscle and heart, while the others 
have comparatively little effect except on the last three. None of 
them are by any means powerful poisons, and fatal intoxication has 
not been observed in man from their use, although very large quanti- 
ties of caffeine have repeatedly caused disagreeable and even alarming 
symptoms. 

Central Nervous System. — In mammals the injection of large quan- 
tities of caffeine is followed by symptoms closely resembling those in- 
duced by strychnine. The reflex irritability is remarkably increased, 
the lightest touch being followed by powerful contraction of almost all 
the muscles of the body. After a time these contractions occur with- 
out any apparent stimulus, and culminate in tonic convulsions which 
last for several seconds. During these the respiration ceases from the 
respiratory muscles being involved in the spasm and occasionally it 
fails to be reinstated when the convulsions pass off. In other instances 
the spasms become weaker and occur at longer intervals ; the respira- 
tion diminishes in frequency and depth and eventually ceases. 

In man, smaller quantities of caffeine stimulate the central nervous 
system, in particular that part associated with the psychical functions. 
The ideas become clearer, thought flows more easily and rapidly, and 
fatigue and drowsiness disappear. Not infrequently, however, con- 
nected thought is rendered more difficult, for impressions follow each 
other so rapidly that the attention is distracted, and it requires more 
and more effort to limit it to a single object. If the quantity ingested 
is small, however, the results are of distinct benefit in intellectual work. 



CAFFEINE. 247 

The capacity for physical exertion is also augmented, as has been dem- 
onstrated repeatedly by soldiers on the march, and more recently by 
more exact experiments with the ergograph. The stimulation of the 
higher nervous centres is often evidenced by the insomnia and restless- 
ness which in many people follow indulgence in coffee or tea late at 
night. Kraepelin has investigated the effects of caffeine from the psy- 
chological point of view, and finds that both tea and coffee facilitate 
the reception of sensory impressions and also the association of ideas, 
especially in fatigue, while the transformation of intellectual concep- 
tions into actual movements is retarded. This he regards as due to 
stimulation of the highest or controlling functions of the brain, caffeine 
acting on the same parts as are first affected by alcohol and the methane 
derivatives, but altering them in the opposite direction. The effects 
of caffeine on the acuteness of the senses has been demonstrated by the 
greater accuracy of touch under its influence. 

Large quantities of caffeine often cause headache and some confu- 
sion, and in rare cases of special susceptibility a mild form of delirium 
may be elicited, or noises in the ears and flashes of light may indicate 
derangement of the special senses. The pulse is quickened, and oc- 
casionally palpitation and uneasiness in the region of the heart are 
complained of. Convulsive movements of the muscles of the hand 
and tremor in different parts of the body have also been recorded in 
some cases. These effects are induced only with difficulty in habitual 
drinkers of tea or coffee, so that the continued administration of small 
quantities of caffeine evidently gives rise to tolerance. 

The symptoms induced by caffeine in the lower mammals are due 
for the most part to its acting on the spinal cord in the same way as 
strychnine, though small doses may act on the brain, for they often 
elicit restlessness and timidity without any marked change in the reflex 
excitability. The centres in the medulla oblongata are also involved 
in the effects, as is indicated by a rise in the blood-pressure from stim- 
ulation of the vaso-motor centre, acceleration of the breathing, and oc- 
casionally some slowness of the pulse from action on the respiratory 
and pneumogastric centres. 

Frogs show no nervous symptoms that cannot be ascribed to action 
on the spinal cord, and in some species these are elicited with con- 
siderable difficulty owing to the muscular action described below. 

On comparing the effects of caffeine and strychnine on the central 
nervous system it will be found that while there is a general similarity 
in their action, the latter causes more marked stimulation of the lower 
divisions and has less action on the cerebrum in mammals and man. 
While they both produce a general increase in the activity of nerve 
cells, caffeine acts more on the psychical, strychnine more on the vital 
and reflex functions. 

Theobromine and the monomethylxanthines have much less effect on 
the central nervous system ; in fact, it is doubtful whether any stimu- 
lation whatever occurs after their use, and xanthine seems to be fol- 
lowed by a rapid loss of reflex irritability in the frog. 



248 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

The Muscular action of caffeine is best seen in the Rana temporaria 
(grass* frog), although it is also induced in other species of frogs, and 
some rigidity may be elicited in mammals by very large doses. When 
a few drops of caffeine are injected into the leg of a frog there follows 
a peculiar stiffness and hardness in the muscles around the point of in- 
jection, which slowly spreads to other parts of the body and induces 
the appearance of rigor mortis. The same effect is observed when 
teased muscle fibres are subjected to a caffeine solution under a high- 
power microscope. The fibres contract, become. white and opaque, and 
look stiff and inflexible ; the transverse striae disappear, while the lon- 
gitudinal become more easily visible. (Fig. 21.) This appearance is 

due to the death and rigor 
Fig. 21. mortis of the fibres. That it 

,„..^ . T is a true rigor is shown by 

I the fact that the ferment 
\A producing ordinary coagula- 
J tion of the myosinogen is 
found increased after the ac- 
tion of caffeine. Furth states 
that the myogen of muscle is 
formed into myogenfibrin and 
"'_1''_-: coagulated by the addition of 
!._ ! /ZferxtTTr^'--- *J4\ caffeine to its solutions out- 

A muscular fibre of the frog (highly magnified). A, side the body, SO that the 
normal ; B, after the application of caffeine solution. The • i i r np • 

coarse striae in B are the folds of the sarcolemma. rigor induced Dy Caiieine 

seems due to a comparatively 
simple reaction between the poison and the proteids of the muscle 
fibre. 

In small quantities caffeine increases the irritability of muscle as 
well as its absolute strength and extensibility, that is, the muscle con- 
tracts on a weaker stimulus and against a greater load than it does nor- 
mally. The amount of work done before fatigue sets in is also in- 
creased, unless when large quantities are applied, when the capacity 
for work is lessened ; and with the first appearance of rigor it ceases to 
react to stimuli altogether. It is frequently stated that caffeine pos- 
sesses no action on the mammalian muscle, but this error is due to the 
fact that much larger quantities are required to induce rigor than to 
paralyze the respiration. If artificial respiration be maintained, stiff- 
ness and hardness of the muscles may be elicited, although complete 
rigor can be produced only by injecting caffeine solution into the 
arteries, as otherwise the heart ceases before the muscles are com- 
pletely contracted. Sobieranski has recently shown that in ordinary 
doses caffeine increases the work done by the human muscles when 
they are stimulated by electric shocks. The universally recognized 
effect of tea and coffee in increasing the capability for physical work 
and in relieving fatigue has generally been regarded as due to changes 
in the nerve cells, but according to Kraepelin and others is really of 
peripheral origin and explained by the direct action on the muscle. 



CAFFEINE. 



249 



While the action of theobromine on the central nervous system is 
much less marked than that of caffeine, muscle enters into rigor after 
the former more readily and xanthine exceeds even theobromine in its 
power to produce this change. 

The action of caffeine on the Circulation is exerted in two directions, 
on the vaso-motor centre in the medulla and on the heart itself. Along 
with the rest of the central nervous system, the vaso-motor area un- 
dergoes stimulation and the smaller arteries are therefore contracted, 
causing a marked rise in the arterial pressure. 

In the frog's heart caffeine in very small quantities is found to in- 
crease the absolute strength, that is, the heart contracts against a 
greater aortic pressure than it would normally, and at the same time 
the amount of blood expelled by each beat is slightly increased. The 
rhythm is generally somewhat accelerated by small doses, but this ef- 

Fig. 22. 




A B 

Tracing of the ventricle of the dog's heart : A, normal ; B, after caffeine. The lever moves upwards 
flaring systole, downwards during diastole. The only alteration caused by caffeine is acceleration. 
The slightly larger excursion in diastole in B is mechanical. (Contrast tracings under digitalis.) 



feet is often of very short duration. On the absorption of larger 
quantities, the heart first becomes slower and its volume smaller, 
then the apex ceases to relax with the rest of the ventricle and 
remains white and contracted, and eventually the whole heart passes 
into a condition of rigor exactly resembling that seen in the skeletal 
muscles. 

When moderate quantities of caffeine are injected intravenously in 
mammals, the heart is accelerated, without any marked change in the 
extent of systole or diastole. The increased rate is independent of any 
action on the regulatory mechanism of the heart, for it is seen in hearts 
in which the accelerans has been cut and the inhibitory apparatus 
paralyzed by atropine. It is probably due to direct action on the 
heart muscle for, as has been stated, an analogous increase in irrita- 



250 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

bility occurs in voluntary muscle. The increased irritability of the 
cardiac fibres also accounts for the fact that stimulation of the vagus 
is followed by less slowing of the heart after caffeine than before its 
administration. In man the heart rhythm is often found slower after 
caffeine, and this appears to be due to stimulation of the inhibitory 
centre in the medulla oblongata, the increased inhibition proving more 
than sufficient to counterbalance the acceleration which would arise from 
the direct action of the caffeine on the heart muscle. After large 
quantities of caffeine the heart becomes weak and irregular and after 
death it is found in diastole. The increased rate of the heart beat is 
not always accompanied by an increase in the amount of blood expelled 
in a unit of time (Bock), although this is often the case. Apparently 
the contractions of the ventricle follow each other so rapidly that the 
time is often insufficient for the inflow of the usual amount of blood. 
The increase in the blood-pressure under caffeine is therefore to be 
ascribed for the most part to the action on the vaso-motor centre, al- 
though not infrequently this is supplemented by an increased efficiency 
of the heart. Theobromine and xanthine possessing but little action in 
the vaso-motor centre, scarcely raise the blood-pressure although they 
have the same effect on the heart as caffeine. 

The Respiration is quickened and strengthened by caffeine, owing to 
a stimulant action on the medullary centre. This effect on the respira- 
tion is seen in the improvement of the respiration in cases of dangerous 
poisoning with alcohol, opium and other drugs which prove fatal by 
failure of the respiration, but is much less marked in normal animals. 

The Temperature has been found to be raised by caffeine through its 
action on the nervous centres and perhaps on the muscles. The in- 
crease is, however, comparatively insignificant (0.5-1° C.) and is seen 
only in eases in which an almost poisonous dose has been used. 

Kidney. — The most important property of caffeine from a thera- 
peutic point of view is its power of increasing the secretion of urine. 

It is an everyday experience that strong coffee or tea increases the 
urine to a much greater extent than the same amount of water, and 
this has been shown to be due to the caffeine contained in these 
beverages. It was formerly supposed that caffeine increased the urine 
in the same way as digitalis, by its action on the circulation, but von 
Schroeder has shown that even when the changes in the circulation are 
prevented from occurring, the same increased flow of urine sets in. 
Caffeine acts directly on the renal epithelium, therefore, and causes 
an increase in the activity which manifests itself by a more rapid secre- 
tion of urine. Not infrequently, however, the administration of caf- 
feine produces no diuresis whatever, in fact less urine may be secreted 
afterwards than before, because besides acting on the kidney, it also 
acts on the vaso-motor centre, and if the consequent contraction of the 
arterioles is great enough, much less blood passes through the kidneys, 
and the epithelial cells, receiving but little fluid, can excrete but little, 
however active they may be. The stimulation of the vaso-motor 
centre may thus entirely prevent any effects from the stimulation of the 



CAFFEIXE. 



251 



renal cells, and in order to produce a satisfactory diuresis measures 
must be taken to prevent the action on the central nervous system. 
This may be done by prescribing along with caffeine some drug which 
lessens the irritability of the medullary 
centres, e. g., chloral, but a much more Fig. 23. 

satisfactory method is to employ the- 
obromine instead of caffeine. As has 
been mentioned already, theobromine 
has little or no effect on the centre, 
while its action on the renal epithelium 
is at least as great as that of caffeine ; 
hence by its use the full effect is got on 
the renal cells without the constriction 
of the vessels. 

When caffeine produces diuresis, it 
causes some dilatation of the renal vessels, 
but this is merely the accompaniment of 
the increased activity of the renal cells 
and is analogous to the dilatation of the 
vessels in a muscle which is undergoing 
contraction. 

In the caffeine diuresis, the fluid part 
of the urine is increased chiefly, but 
the solids also undergo an augmentation, 
though not to the same extent. Among 
the solids the chief increase is seen in 
the sodium chloride, the nitrogenous 
constituents undergoing less alteration 
although they also rise in amount ; a 
small amount of sugar is often found 
in the urine, more especially if the food 
has contained large quantities of sugar- 
forming substances, but this glycosuria 
is probably due merely to the large quan- 
tities of fluid sweeping some of the sugar 
of the blood along with it, and does 
not indicate any dangerous alteration in 
the renal epithelium or in the metab- 
olism. 1 

The excretion of large quantities of 
fluid in the urine is, of course, accom- 
panied by a diminution of the fluids of 
the blood, but the latter soon recuperates 
itself from the tissues. If there is any 
accumulation of liquid, such as oedema, it 
is drained into the blood to replace the 

1 Richter's view that caffeine induces glycosuria through alteringthe glycogenic func- 
tions of the liver, scarcely appears admissible (Ztschr. f. klin. Med., xxw., p. 463). 



B 



C 



Caffeine diuresis in a rabbit. The 
amount of uriue passed in ten minutes 
is represented by the height of the rec- 
tangles. The first of these, A-B, repre- 
sent the normal secretion. At B a small 
dose, and at C a large dose of caffeine 
was injected intravenously, and the 
secretion is accordingly increased. The 
shaded part of the rectangles represents 
the amount of solids in the urine. It 
will be noted that these are increased but 
not to the same extent as the fluid. The 
dotted line represents the average 
height of the blood-pressure during each 
period often minutes. The animal had 
received a large dose of chloral to de- 
press the vaso-motor centre and the 
heart, and caffeine had, therefore, little 
or no effect ou the height of the hlood- 
pressure. 



252 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

fluid thrown out by the kidney, and caffeine may accordingly be used 
to remove oedema or dropsy in this way. If no such accumulation 
exists, the blood draws on the fluids of the intestine and stomach, and 
their withdrawal leads to the sensation of thirst. As a diuretic, 
caffeine is distinctly inferior to theobromine ; in the first place because 
the diuresis is less certain and is often accompanied by nervous symp- 
toms — sleeplessness and restlessness — and secondly because the in- 
crease in the secretion is smaller and lasts for a shorter time. 

Excretion. — Caffeine is excreted in the urine to a very small extent 
as such. During its passage through the body it loses its methyl 
groups and first becomes dimethyl- and then monomethylxanthine. 
Eventually xanthine is formed and this probably breaks up into urea. 
In the urine are found small quantities of the unchanged drug, 
accompanied by larger quantities of dimethylxanthine, heteroxanthine 
and xanthine. After theobromine, some of the unchanged drug is 
found in the urine along with heteroxanthine and xanthine. 

The exact order in which the methyl groups are lost in the tissues ap- 
pears to differ in different animals ; in the dog all three isomeric di- 
methylxanthines are formed from caffeine and after large doses appear in 
the urine, although theophylline predominates, while in the rabbit and in 
man paraxanthine is formed in larger amounts. The monomethylxanthines 
are also excreted in different proportions in different animals, heteroxanthine 
prevailing in man and the rabbit. 

Preparations. 

Caffeina (U. S. P., B. P.), long, white, silky crystals, without odor, but 
possessing a bitter taste, but little soluble in cold water, more so in alcohol, 
still more so in boiling water. 0.05-0.3 G. (1-5 grs.). 

Caffeina Citrata (U. S. P.), Caffeine Citras (B. P.), a white powder, 
consisting of a weak chemical combination of citric acid and caffeine. It is 
decomposed by mixture with more than 3 parts of water. 0.1-0.5 G. 
(2-8 grs.). 

Caffeina Citrata Effervescens (U. S. P.), Caffeine Citras Effer- 
vescens (B. P.), a mixture of citrated caffeine with sodium bicarbonate, tar- 
taric acid and sugar. On throwing the powder in water it effervesces, 
owing to the acids acting on the bicarbonate and liberating carbonic acid. 
This preparation is an extremely weak one, containing only 1 per cent, of 
caffeine in the U. S. P. and about 2 per cent, in the B. P. 

Caffeine is best prescribed either in powder or in tablets formed from 
either of the first two preparations. It may also be given in water with 
salicylate of soda, Avhich aids its solution. 

Theobromina (unofficial) is a crystalline powder even less soluble than 
caffeine, and is absorbed with difficulty when given alone. It is generally 
prescribed in doses of 0.5 G. (8 grs.) three times a day, but larger quantities 
may be given. Solutions of salicylate of soda dissolve it much more readily 
than pure water. 

Diuretin consists of a mixture of equal parts of theobromine-sodium and 
salicylate of sodium and is much more soluble than theobromine. The dose 
is 1 G. three times a day, either in powder form or in solution. Neither 
theobromine nor diuretin is pharmacopceial. 

Guar ana (U. S. P.), a brown paste derived from the seeds of Paullinia sor- 
bilis and containing caffeine and theobromine along with some tannic acid. 

Extractum Guaranse Fluidum (IT. S. P.), 3-8 c.c. 



CAFFEINE. 253 

Numerous preparations of Kola nut are now put on the market, but the 
pure principles are preferable. 

Therapeutic Uses. — The action of caffeine on the central nervous 
system has led to its employment in a number of different conditions. 
Thus, in nervous exhaustion it may be used to stimulate the brain, and 
in collapse its action on the vaso-motor and respiratory centres has been 
found of value — the blood-pressure rises, the whole tone of the circu- 
lation is improved and the respiration becomes quicker and less shallow. 
In narcotic poisoning with failing respiration, caffeine may be used to 
stimulate the centre in place of strychnine or atropine ; in opium 
poisoning more particularly, strong coffee has long been used, but 
caffeine might be substituted with advantage. Its stimulant action on 
the brain, and more especially on the respiration, renders it an antidote 
in dangerous cases of alcoholic poisoning also. Some forms of migraine 
and headache are relieved by caffeine, but in others it seems rather to 
intensify the pain. Kola preparations are often advised as general 
tonics in weakness and neurasthenia. 

Caffeine has been used largely for its action on the heart and is often 
said to be a substitute for digitalis, though as a matter of fact, it can- 
not replace the latter, the action of the two on the heart being entirely 
dissimilar. In cases of heart weakness without marked dilatation and 
incompetency of the valves, it may be of service as it increases the 
activity of the ventricle, but its reputation in cases of cardiac disease 
is due mainly to the removal of dropsy through its diuretic action. 
The contraction of the arterioles following the use of caffeine may also 
be of service in feeble action of the heart. 

In their action on the kidney the members of the caffeine series 
stand preeminent, no other drug producing such a copious flow of urine 
as either caffeine or theobromine. As has been explained already, the 
latter is to be preferred to caffeine as a diuretic, and may be used in 
all cases in which there is a pathological accumulation of fluid in the 
body, whether of cardiac, hepatic or renal origin. The results are 
most brilliant, however, in cases of cardiac dropsy, and here it may 
be prescribed along, with one of the digitalis series. It must be em- 
phasized, however, that in these cases it cannot supplant digitalis, but 
merely aids in the removal of the fluid which is obstructing the circu- 
lation by its pressure, while digitalis relieves the dilatation of the heart. 
In cases of hepatic dropsy, caffeine and theobromine have also proved 
of service, although here the treatment can only be considered palliative. 
In renal dropsy theobromine has been used with somewhat variable 
results ; it does not seem to increase the albumin in the urine, but 
not infrequently little or no diuresis follows its administration. This 
is only to be expected where the renal cells are in such a condition as 
to be incapable of stimulation. Where the disease is less developed 
the members of this series produce the usual increase in the se- 
cretion. 

Inflammatory effusions do not seem to be lessened to any marked 
extent by either caffeine or theobromine. 



254 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

Theobromine in very large doses has been found to produce nausea 
and loss of appetite when taken for long, but in ordinary quantities it 
produces no symptoms save diuresis. 

A number of other derivatives of xanthine and caffeine have been isolated 
but none of them have been used in therapeutics, and some doubt exists as to 
their relative activity in the body. None of the xanthine bodies appear to 
possess the action of caffeine on the central nervous system, though another 
purine derivative, desoxycaffeine excels it as a stimulant. Xanthine itself 
and all its monomethyl and dimethyl derivatives hitherto examined induce 
muscle rigor. According to Ach, the latest writer on the subject, the di- 
methyl-xanthines are more powerful diuretics than caffeine, and theophylline 
and paraxanthine surpass even theobromine in their action on the kidney. 
The monomethylxanthines and xanthine itself are only slightly diuretic. 
Guanine, a substance nearly allied to the xanthine series in its chemical 
form, seems to have practically no action on frogs. 

A number of compounds of caffeine have been proposed as substitutes for 
it, the object being to provide a drug possessing its diuretic action but with- 
out its effects on the central nervous system. Of these, sodium-caffeine sul- 
phonate (symphorol), is the best known, but it possesses no advantages over 
theobromine and may therefore be regarded as superfluous. It acts less on 
the central nervous system than caffeine and is thus an example of the 
general law that the action of drugs is lessened by the addition of the sul- 
phon group. 

Coffee and Tea. 

Coffee is not used in medicine, but in view of its immense dietetic 
importance it may be mentioned here in what respects it differs from 
the pure caffeine. The coffee bean contains about § per cent, caffeine, 
and the roasting does not seem to reduce the percentage at all, as was 
formerly supposed, and since almost all the caffeine is extracted by the 
ordinary culinary preparation, a cup of coffee contains from 0.1—0.2 G. 
(1J-3 grs.) of caffeine. Along with the caffeine there are extracted a 
number of other substances, the most important of which are volatile 
substances produced by the roasting, which have been called Coffeon 
and resemble in their action the volatile oils. 

Tea contains a larger percentage of caffeine (about 1J-2 per cent.), 
but as less tea is used than coffee, each cup may be considered to con- 
tain 0.1—0.2 G. (1J-3 grs.). In green tea there is a considerable 
quantity of a volatile oil which also passes into the infusion, but this 
is not present in black tea, owing to the greater heat used in its manu- 
facture. Both black and green tea contain about 7 per cent, of tannic 
acid, but this is only extracted slowly. The bitter taste in tea that 
has been prepared too long is due to the tannic acid passing into solu- 
tion. 

The wakefulness and the relief from fatigue which are produced 
by tea and coffee are undoubtedly due to the caffeine contained in 
them, and are to be ascribed to the central action chiefly, although 
its action on the muscles may also be of some value here. On the 
other hand, the feeling of well-being and comfort produced by coffee 
after a full meal is probably to be explained by the local action of the 
volatile oil in the stomach. The same result is produced by prepara- 



CAFFEINE. 255 

tions of the other volatile oils, and, in fact, these are often added to 
coffee in the form of brandy and other liqueurs. Apart from this local 
action the volatile parts of tea and coffee (theon, coffeon) seem to have 
no effect whatever on the economy. In experiments on the activity 
of the digestive ferments outside the body, it is found that caffeine 
increases slightly the rapidity of the process, but that coffee and tea 
retard it considerably. On the other hand, coffee, probably owing to 
its volatile oils, increases the peristaltic movements of the intestine 
while caffeine has no effect on them. Tea that contains much tannic 
acid precipitates the peptones and albumins of the stomach, and may 
lead to chronic dyspepsia and constipation. 

It was formerly stated that coffee lessened the tissue change and 
that it ought therefore to be included among foods, and one enthusiast 
even suggested that a diet of tea and coffee exclusively should 
be served out in the besieged fortresses of France in 1870. It has 
been shown conclusively, however, that far from lessening the metab- 
olism of the body, coffee and tea increase it, the amount of urea and 
carbonic acid excreted being considerably augmented by their use. 
This is only to be expected from the increased activity of the nervous 
centres, which leads to increased movement and increased consump- 
tion. 

Chocolate contains theobromine (0.5-1 per cent.), instead of caf- 
feine, and besides this a large amount of fat (cacao-butter 30-50 per 
cent.), starch and albumins. The theobromine does not possess the 
stimulant action of caffeine on the nervous system, and chocolate may 
therefore be taken where coffee or tea produces wakefulness. The 
starch and fat are assimilated by the tissues so that chocolate is a true 
food. At the same time the cacao-butter is not easily absorbed from 
the stomach, and may give rise to heaviness and discomfort, and even 
to indigestion. Chocolate is, therefore, often used freed from the oil, 
but theobromine is also somewhat detrimental to the gastric mucous 
membrane after continued use. 



Bibliography. 

Johannsen. Ueber die Wirknngen des Koffeins, Inaug. Diss., Dorpat, 1869. 

Aubert. Pfliiger's Arch. f. Physiol., v., p. 589. 

Schmiedeberg. Arch. f. exp. Path., ii., p. 62. 

Archangelsky. Arch, internat. de Pharmacodyn., vii., p. 405. 

Bock. Arch. f. exp. Path., xliii., p. 317. 

Filehne. Arch. f. Anat. imd Phys., 1886, p. 72. 

v. Sehroeder. Arch. f. exp. Path., xxii., p. 39 ; xxiv., p. 85. 

Albcmese. Ibid., xxxv., p. 449 ; xliii., p. 305. Bericht. d. deutsch. Chem. Gesell., 
1899, p. 2280. 

Bondzynski u. Gottlieb. Arch. f. exp. Path. u. Pharm., xxxvi., p. 45 ; xxxvii., p. 385. 

Heerlein. Pfliiger's Arch., Hi., p. 165. 

Philipps and Bradford. Journ. of Physiology, viii., p. 117. 

Dreser. Arch. f. exp. Path. u. Pharm., xxiv., p. 221. 

Sobieranski. Gazeta lekarska, 1896. Centralbl. f. Physiol., 1896, p. 126. 

Kmepelin. Ueber die Beeinflussung einfacher psychischer Yorgange durch einige 
Arzneimittel (Jena, 1892) and Psychologische Arbeiten, i., p. 378 ; iii., p. 203. 

Hellin u. Spiro. Arch. f. exp. Path. u. Pharm., xxxviii., p. 368. 

Brunton and Cash. Jonrn. of Phys., ix., p. 112. 



256 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

Lehmannu. Wilhelm. Arch. f. Hygiene, xxxii., p. 310. 
Lehmann u. Tendlau. Ibid., p. 327. 
Riegel. Congress f. inn. Med., 1884, , p. 292. 
Pawimky. Ztschr. f. klin. Med., xxiii., p. 440; xxiv., p. 315. 
Fischer. Per. d. deutsch. chem. Gesell., xxx., p. 549. 
v. Fv.rth. Arch. f. exp. Path. u. Pharm., xxxvii., p. 389. 

Kriiger. Bericht. d. deutsch. chem. Gesell., 1899, pp. 2818, 2677, 3336. Arch. f. 
exp. Path. u. Pharm., xlv., p. 259. Ztschr. f. phys. Chem., xxi., p. 169. 
Ach. Arch. f. exp. Path. u. Pharm., xliv., p. 319. 
Katsuyama. Ztschr. f. phys. Chem., xxxii., p. 235. 

Cushny and Van Naten. Arch, internat. de Pharmacodynamic, ix., p. 169. 
Anten. Ibid., viii., p. 455. 
Santesson. Skandin. Arch. f. Physiol., xii., p. 259. 

IX. CURARA. 

Curara, woorara, urari or woorali, is an arrow poison used by the 
natives of South America, who prepare it by extracting various barks 
and plants. The plants used seem to vary somewhat in different local- 
ities, but those which produce the symptoms known as curara action 
are undoubtedly members of the genus Strychnos, such as S. toxifera. 
Different preparations of curara were found by Boehm to contain 
different alkaloids. That formerly obtainable owed its activity to Oura- 
rine, but the curara now exported contains Tubocwarine, which resem- 
bles curarine in its action, and Curine, a weaker poison, which has an en- 
tirely different effect. Another preparation examined by him contained 
three alkaloids, Protocurine, Protocuridine and Protocurarine, the last of 
which is the most powerful of all the curara alkaloids. Most of the 
experiments on which the statements regarding curara action are ba^ed, 
were performed by the crude drug, but the alkaloids seem to have a 
very similar effect, with the exception of curine. 

Action. — The chief effect of curara is paralysis of the Terminations 
of the Nerves Supplying Striated Muscle, and it therefore causes general 
paralysis of all the voluntary movements. In the mammal the mus- 
cles give way one after the other until the animal lies helpless on the 
ground. It can still move its limbs, but cannot recover its ordinary 
position, and soon the limbs become totally paralyzed and the respiratory 
movements alone persist, although they too are slow, weak and jerky. 
Eventually the respiration ceases also and asphyxia follows, but is 
not betrayed by the usual convulsions, owing to the paralysis of the 
motor nerve ends. The blood, however, becomes venous, and the heart 
soon fails from the asphyxia and not through the direct action of the 
poison. 

In the frog similar symptoms are seen, but here the arrest of the 
respiration is not necessarily fatal, as the skin carries on the exchange 
of gases, and recovery not infrequently occurs after two or even five 
days of complete paralysis. The cause of the curara paralysis was dem- 
onstrated by the classical researches of Claude Bernard and Kolliker. 
If the sciatic nerve of the frog be stimulated during the paralysis no 
movement follows, but if the artery of one leg be ligatured before the 
application of the poison this limb remains unparalyzed and reacts to 
reflex irritation, while the rest of the body is perfectly motionless. 



OUBABA. 257 

These facts can only be interpreted in one way ; the paralysis is peri- 
pheral and not central, and may, therefore, be due to action either on 
the muscle, the nerve trunks, or the intermediate structures. That 
it is not due to the muscle is shown by the fact that direct stimu- 
lation causes the same movement as usual. On the other hand, in the 
experiment in which the artery is ligatured, stimulation of the nerves 
above the ligature, that is, where the poison has access to the nerve 
fibres, causes contraction, so that the nerve trunks do not seem affected. 
This may be shown in another way ; if a nerve-muscle preparation be 
made and the nerve be laid in a solution of curara, contraction of the 
muscle still occurs on stimulation of the nerve, but if the muscle be 
laid in the curara solution stimulation of the nerve has no effect while 
direct stimulation still causes contraction. Curara must, therefore, act 
on the connection between the nerve and muscle within the muscle it- 
self, that is, on the terminations of the nerve in the muscle. Curara 
paralyzes the nerve terminations without previous stimulation. 

Here, perhaps, better than elsewhere it can be shown that the condition 
of •• paralysis " produced by poisons is analogous to that termed by physiol- 
ogists u fatigue." It is known that on stimulating a nerve rapidly by elec- 
tric shocks, or otherwise, the muscle at first contracts with every stimulation, 
but eventually ceases to respond, owing to " fatigue" of the nerve ends, 
that is. to their inability to transmit impulses from the nerve to the muscle. 
If now the response to nerve stimulation of a muscle to which a minute 
quantity of curarine has been applied, be compared with that of a normal 
one, it is found that the poisoned one ceases to respond much sooner than 
the other — i. e. , its nerve ends become fatigued much sooner. The more cu- 
rara is applied, the sooner does it fatigue, until at last no response at all can 
be elicited from it. The ' ' paralysis ' ' of the nerve terminations by curara 
then is of the same nature as physiological "fatigue," and other conditions 
of " paralysis " are also analogous to those produced by over-stimulation, 
though the exact condition of the paralyzed organ may not be the same as the 
fatigued one. Thus there is some reason to suppose that in the curarized 
terminations the energy consumed in transmission is present, but in such a 
form that it cannot be changed to actual movement, while in fatigue the 
energy has all been exhausted by the impulses which have already passed 
through. 

Curara paralyzes very readily the terminations of nerves in all striped 
muscular tissue except the heart. Tbe nerves first affected are those 
of the short muscles of the toes, ear and eye, later those supplying 
the limbs, head and neck, and, last of all, those supplying the muscles 
of respiration. At first, slight movements can be performed, because 
single impulses can pass through the nerve ends, but sustained con- 
tractions such as are necessary to preserve the equilibrium, cannot be 
maintained, and the animal therefore falls. The intermittent impulses 
to the respiratory muscles still allow time in the interval for the re- 
covery of the terminations, but as the intoxication proceeds, the num- 
ber of impulses which can pass through becomes fewer and fewer, and 
the movement therefore assumes more and more the character of a jerk. 
Eventually total paralysis sets in and, unless artificial respiration is 
carried on, asphyxia follows. Small doses of curara do not affect the 
17 



258 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

innervation of unstriped muscle, and the strict demarcation of its action 
is seen very distinctly in organs which consist partly of striated and 
partly of unstriated fibres. Thus in the oesophagus, the striated muscle 
fibres no longer contract on stimulation of the vagus after curara, 
while the unstriated continue to respond as usual. In the iris of the 
mammals, which consists of unstriated muscle, curara has no effect, while 
the striated muscle of the bird's iris ceases to respond to stimulation of 
the motor oculi, but contracts on direct stimulation. The terminations 
of the nerves in the heart are not affected, as the cardiac fibre is not of 
the same character as the ordinary striated one, but the nerves of the 
lymph hearts of the frog are paralyzed, these organs consisting of ordi- 
nary striated muscle. Curiously enough, it has been found that curara 
does not act on the terminations of the motor nerves supplying the elec- 
trical organ of the torpedo, although this organ is analogous to striated 
muscle in many respects. The nerve ends in striated muscle in in- 
vertebrates also appears to be immune to curara (Straub). 

The nerve fibres seem unaffected by curara, for stimulation causes 
the usual electrical changes in them after it. The action of curara on 
the muscle fibres has been a good deal disputed, many authorities deny- 
ing that any alteration whatsoever occurs, while others assert that slight 
modifications may be observed. The irritability to direct stimulation 
seems rather less, but this is due to the paralysis of the nerve ends. 
The contraction is often said to be somewhat prolonged and weakened, 
and the absolute strength to be diminished, but these changes are in 
any case very slight and unimportant. 

When larger quantities of curara or curarine are injected, several 
other organs are affected. Thus the Peripheral Ganglia cease to trans- 
mit impulses, and hence stimulation of the nerves central to them has 
little or no effect. In this way the stimulation of the vagus in the 
neck produces no slowing of the heart, because the impulses can no 
longer pass through the ganglionic structures on the course of the 
fibres, and stimulation of several secretory nerves, such as the chorda 
tympani, has no effect on the secretion. In the same way, stimulation 
of the cervical sympathetic no longer dilates the pupil, and ,the 
splanchnic nerve loses its control over the mesenteric vessels and the 
movements of the intestine. The sympathetic ganglia are also para- 
lyzed by nicotine, which differs from curara in stimulating them pre- 
viously, and also in attacking the ganglia before it affects the endings 
in muscle. 

Large quantities of curara are often said to paralyze the nerve 
terminations in unstriated muscle, but this has never been satisfactorily 
proved, all the symptoms quoted to show this effect being explained 
by the paralysis of the sympathetic ganglia, which undoubtedly occurs. 

Curara, then, first paralyzes the terminations of efferent or centri- 
fugal nerves in voluntary muscle, and in larger quantities the ganglia 
(c£ Nicotine). The peripheral terminations of the afferent or sensory 
nerves seem unaffected, for if the artery of one leg be ligatured before 
the application of curara, reflex movements may be obtained in it from 



CTJRARA. 259 

stimulation of any part of the body, while if the sensory terminations 
were paralyzed reflexes could be elicited only by the irritation of parts 
to which the poison had not penetrated, i. e., from the ligatured leg. 

Yery large quantities of curarine are said by Tillie to cause a stim- 
ulation of the Central Nervous System resembling that described under 
strychnine. In ordinary poisoning, however, no evidence of this 
stimulation is shown, as although an increased Dumber of impulses 
may be sent out, they cannot reach the peripheral organs owing to the 
paralysis of the motor end-plates and of the ganglia. If, however, 
curarine reach the central nervous system without affecting the mus- 
cles, spasmodic contractions and increased reflexes occur exactly as in 
strychnine poisoning. This is seen when curarine is perfused through 
the vessels of the cord or when it is applied to it without the aid of the 
circulation, but the quantity required to stimulate the cord is much larger 
than that which suffices to paralyze the terminations of the motor nerves. 

The Heart does not seem to be acted on directly by ordinary quan- 
tities of curarine, and the circulation is left intact long after the 
respiratory nerves have been paralyzed. Large quantities prevent 
the inhibitory action of the vagus, and the pulse is consequently 
quickened, but the blood-pressure often begins to fall at the same time, 
owing to the dilatation of the peripheral arteries through paralysis of 
the ganglia on the course of the constrictor nerves. After curara and 
curarine the movements of the Intestines are said to be increased. 
This was formerly supposed to be due to the asphyxia, but seems to 
be independent of it, for the increased peristalsis occurs even when 
artificial respiration is kept up, and, according to JNasse, the irritability 
of the bowel muscle is much increased by curara. A similar accelera- 
tion of the rhythmic movements of the spleen has been noted after 
curara by Shafer and Moore. 

The Secretions sometimes seem to be increased by curara, for tears, 
saliva and perspiration may be formed in considerable excess of the 
normal, but no explanation has been offered and it may possibly be 
due to the asphyxia and not to any direct action. 

The paralysis of the ends of the motor nerves leads to a very 
marked decrease in the products of Tissue Change. Thus, the carbonic 
acid excreted and the oxygen absorbed amount to only J-f of the 
normal, because the impulses which pass to the muscles and maintain 
their metabolism in the normal animal, are prevented from reaching 
them through the paralyzed terminations. This change, it must be 
noted, is not due to any direct action in the muscular fibres but merely 
to the impulses from the central nervous system being cut off. 

Another alteration of the tissue change often produced by curara is 
evidenced by the appearance of sugar and lactic acid in the urine. 
This glycosuria is not, however, a direct effect of the drug, but is due 
to the asphyxia. From the same cause the glycogen of the liver and 
muscles disappears entirely soon after the administration of curara. 

Curara is excreted by the kidneys, apparently unchanged. It has 
long been known that this arrow poison may be swallowed with impu- 



260 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

nity provided there is no wounded surface in the mouth or throat and 
that it is therefore perfectly safe to suck the poison from a wound. 
This has been explained in various ways, some holding that the ab- 
sorption from the stomach is so slow that the kidneys are able to ex- 
crete the poison as fast as it reaches the blood and that this prevents its 
accumulation in sufficient quantity to affect the tissues. Others suppose 
that the liver retains and destroys it and a third view is that it i> ren- 
dered innocuous in passing through the stomach walls. The results of 
different investigators differ so widely in regard to these explanations 
that it is impossible to state definitely which is correct, and it is not un- 
likely that more than one factor is engaged. 

Rothberger has recently shown that curara and physostigmine are 
mutually antagonistic so far as the action on the nerve terminations in 
striated muscle is concerned (see Physostigmine). 

Curine, the second alkaloid found by Boehm in some specimens of curara, 
is a much less poisonous body than curarine. It possesses some action on 
the heart, the same appearances following its injection in the frog as after 
digitalin and veratrine, while in mammals the rhythm is slow even after 
paralysis of the inhibitory mechanism. 

Preparations. 

Curara, an extract of varying constitution and strength. The active con- 
stituents are freely soluble in acidulated water, and when used ought to be 
injected hypodermically. Before using curara in therapeutics it is always 
necessary to estimate the strength of the preparation by experiments on 
animals, and its application ought to be graduated, commencing with the 
smallest quantities and increasing them until the desired effect is attained. 
Neither curara nor its alkaloids are recognized by any of the official pharma- 
copoeias. 

Therapeutic Uses. — Curara has been used occasionally in various condi- 
tions of exaggerated movement, such as tetanus, strychnine poisoning and 
hydrophobia. The object is to lessen the movement by partial jmralysis of 
the motor terminations. The respiratory nerves being the last to be affected 
by the poison, the convulsions may be controlled, or at any rate hindered 
from causing such marked irregularity of the respiration as they would 
otherwise do, and in the same way the overstrain of the heart caused by the 
convulsions may be prevented. The danger accompanying the use of curara 
is great, however, and the fact that in all these cases the cause of the move- 
ment is excessive activity of the central nervous system would seem to indi- 
cate one of the many depressants of that system, rather than a drug such as 
curara, whose action is on an entirely different part of the body. Some 
cases of tetanus and one of hydrophobia are alleged to have been successfully 
treated by it, but its use must still be regarded as purely experimental, and, 
in fact, as generally opposed to the teachings of rational therapeutics. 

Paralysis of the terminations of the motor nerves in striated muscle — the 
so-called " Curara- Action " — is elicited by a large number of poisons, but in 
few of them is it the first effect of their application. Many drugs induce it 
only when injected in large quantities and at the end of a series of phenom- 
ena produced by their action on other parts of the body ; it is observed much 
more frequently in frogs than in mammals, and is often of little importance 
compared to the other symptoms. Among the bodies which resemble curara 
more closely in their action, the peripheral paralysis playing the chief role 
in their effects, are the compounds formed from the natural alkaloids by the 



CONIINE, GEISEMININE AND SPARTEINE. 261 

substitution of an alkyl, e. g., methylstrychnine, amylquinine, etc. 1 Some 
of the ammonium salts and many of the alkyl ammonium combinations also 
cause it, so that the general statement may be made that quaternary 
compounds of nitrogen possess a curara action ; in these the nitrogen atom 
may be replaced by phosphorus or arsenic without loss of the curara action, 
so that nitrogen is not a necessary constituent of substances possessing this 
property. The simpler bodies, pyridine and quinoline which form the basis 
of most of the natural alkaloids, have little action save on the nerve ends, a 
fact which is of some importance in the consideration of the relation between 
the chemical constitution and the pharmacological action of poisons. At 
the same time the property of causing this paralysis is so widespread among 
substances of very different constitution that it may be looked upon as in- 
dicating a peculiar susceptibility and weakness of the motor terminations, 
more especially in the lower vertebrates, and inferences based upon it as to 
the mutual relation of substances are to be received with caution (San- 
tesson). 

Bibliography. 

CI. Bernard. Comptes rendus, xxxi., p. 533; xliii., p. 825. 
Kolliker. Virchow's Archiv, x., p. 3. 
Kuhne. Arch. f. Anat. und Phys., 1860, p. 477. 
Nasse. Beitrage zur Phys. der Darmbewegung, Leipzig, 1866. 
Boehm. Beitrage zur Physiologie C. Ludwig zu seinem sechzigsten Geburtstage 
gewidmet, Leipzig, 1887, p. 173. Arch, der Pharmacie, ccxxxv., p. 660. 
Overend. Arch. f. exp. Path. u. Pharm., xxvi., p. 1. 
Tillie. Ibid., xxvii., p. 1. 
Boehm. Ibid., xxxv., p. 16. 

Santesson. Ibid., xxxv., p. 23. Skand. Arch. f. Physiol., x. and xi. 
Sauer. PA tiger's Arch., xlix., p. 423. 
Zuntz. Ibid., xii., p. 522 
Nikolski u. Dogiel. Ibid., xlvii., p. 68. 
Jakabhazy. Arch. f. exp. Path. u. Pharm., xlii., p. 10. 
Morishima. Ibid., p. 28. 
Straub. Pfluger's Arch., lxxix., p. 379. 



X. CONIINE, GELSEMININE AND SPARTEINE. 

Several alkaloids which show many points of resemblance to curara 
in their pharmacological effects, may be classed together,, although their 
action may differ in details. 

Coniine. 

Coniine is one of the simpler derivatives of Piperidine, which is 
obtained from Pyridine by reduction. A series of alkaloids may be 
formed from piperidine by substituting methyl, ethyl, propyl or other 
alkyls for hydrogen, and one of these, a-propyl-piperidine, is the 
natural alkaloid coniine. 

Pyridine. Piperidine. Coniine. 

CH CH 2 CH 2 

Hc/\CH H 2 C/ \CH 2 H 2 C/ \CH 2 

hc'n^/'ch h^/'ch,, H^/CH-C^ 

N NH NH 

1 Boehm has recently stated that tubocurarine, which is the active constituent of 
much of the modern curara, is really one of those methyl bases (methylcurine). 



262 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

Coniine is found in Hemlock (Conium maculatum), along with two 
nearly allied alkaloids, Methylconiine and Conhydrine. The latter dif- 
fers from coniine only in having a hydroxyl group in the side chain. 
Methylconiine is found in many specimens of coniine, and is probably 
formed in the plant, although this has not been definitely proved; in 
it the hydrogen attached to the nitrogen of coniine is replaced by 
methyl. Coniine is of some historical importance, as the first vegetable 
alkaloid which was successfully formed by synthesis in the laboratory. 
It is a volatile fluid, characterized by a strong mouse-like odor, but 
forms crystalline, non-volatile salts. The two other alkaloids of hem- 
lock act in the same way as coniine, although much more weakly, so 
that the effects of the crude preparations of the plant are identical 
with those of coniine. 

Piperidine and its compounds with methyl and ethyl-act in the same 
way as coniine but more weakly. An ascending scale of toxicity may 
be formed, commencing with piperidine and passing upwards through 
methyl- and ethyl-piperidine to coniine. The other simple derivatives 
of piperidine seem to resemble coniine in their action as far as it has 
been investigated. 

Symptoms. — The general symptoms induced in man by poisonous 
doses of coniine are weakness, languor and drowsiness which does not- 
pass into actual sleep. The movements are weak and unsteady, the 
gait is staggering, and nausea and vomiting generally set in, along with 
profuse salivation. In most cases the intelligence remains clear to the 
end, as is related of the death of Socrates from hemlock poisoning, 
but in some instances imperfect vision and hearing have been noted. 
The pupils are somewhat dilated. Tremors and fibrillary contractions 
of the muscles are often seen in animals, and some observers state that 
actual convulsions occur. The breathing becomes weaker and slower 
and death occurs from its arrest. 

Action. — Coniine is sometimes credited with possessing a narcotic 
depressant action on the Central Nervous System, but this is by no 
means a characteristic feature in poisoning, for in both man and 
animals consciousness is often retained until immediately before the 
cessation of the respiration. Other writers mention convulsions as a 
feature of coniine poisoning, and weak convulsive movements are often 
seen before death, obviously from the failure of the respiration. 
Quite distinct from these are the twitching and tremors of the earlier 
stages of the intoxication, which are often accompanied by a certain 
stiffness and rigidity of some of the muscles of the limbs. Some of 
these movements may be due to the partial paralysis of the motor 
nerve terminations preventing the animal from contracting its mus- 
cles in a normal tetanus and permitting only of short, jerky move- 
ments, which may readily be mistaken for convulsions. But at the 
same time, the tremor and the rigidity of the limbs seem to indicate 
some central stimulation, although this point requires further investi- 
gation. This preliminary stimulation may afterwards pass into de- 
pression of the lower parts of the central nervous system, although this 






CONUNK 263 

is denied by some investigators, who maintain that coniine has little 
or no central action, but manifests its activity only in the peripheral 
organs. 

Coniine causes nausea and very often vomiting at an early stage of 
its action. This may be elicited by its hypodermic or intravenous in- 
jection, and is probably due to an alteration in the medullary centres 
rather than in the stomach. The nausea is accompanied by profuse 
salivation and sometimes by perspiration. 

The chief effect of coniine in the frog is a paralysis of the Termina- 
tions of the Motor Nerves similar to that induced by curara. This 
paralysis is elicited only with difficulty in the mammal, but unques- 
tionably occurs to a more or less marked extent. According to some 
researches on the subject, all the symptoms in mammals are due to the 
paralysis of the ends of the motor nerves, while others regard both the 
convulsions and the final failure of the respiration as of central origin. 
It seems likely that while in the frog the symptoms are all due to the 
action on the nerve terminations, some of the phenomena observed in 
mammals are due to central stimulation and to subsequent paralysis of 
the medullary centre of respiration. It is difficult to explain on any 
other theory how the symptoms of coniine poisoning are so different 
from those of curara. 

Coniine acts on the Peripheral Ganglia in the same way as curara. 
According to some writers these are first stimulated and then para- 
lyzed, and there seems to be no question as to the final paralysis, 
whether the preliminary stimulation is present or not. Coniine cer- 
tainly does not act so strongly on the ganglia as nicotine, and the 
details of the action may, therefore, be left for discussion under that 
heading. (See page 274.) The inhibitory impulses no longer reach 
the heart after large doses of coniine, owing to paralysis of the gang- 
lionic apparatus and stimulation of the vagus nerve has no effect on 
the pulse rate. Some drugs which act on the extreme terminations of 
the inhibitory fibres still slow and weaken the heart, however. Simi- 
larly, stimulation of the cervical sympathetic no longer dilates the 
pupil, because the superior cervical ganglion is paralyzed. The partial 
dilatation of the pupil in cases of poisoning may, perhaps, indicate a 
similar action on the ciliary ganglion. 

Coniine seems to have but little direct effect on the Heart though 
large quantities slow the rhythm and somewhat prolong the systole in 
the frog (Moore and Row), and some slowing of the mammalian heart 
has been noted from the intravenous injection of large quantities. The 
inhibitory mechanism is often found to be stimulated and the pulse is 
accordingly somewhat slow and w r eak. The paralysis of the ganglia 
on the inhibitory nerve may lead to some acceleration in other cases, 
but the changes in the heart are not marked features in the intoxica- 
tion. 

Moore and Row have observed a very considerable though transient 
increase in the arterial tension after coniine, and regard it as of pe- 
ripheral origin, for they found that the perfusion of coniine through 



264 ORGANIC DRUGS ACTING • AFTER ABSORPTION. 

the blood vessels of the frog tends to constrict them, while the direct 
application to the exposed blood vessels has no such effect, but rather 
widens their calibre. They are accordingly inclined to regard the rise 
of blood -pressure as due to a stimulation of the ganglionic apparatus 
lying on the course of the vaso-constrictor nerves. 

The Respiration is generally accelerated and deepened in the earlier 
stages of the coniine intoxication, but later becomes slow and labored, 
then weak and irregular, and finally ceases while the heart is still strong 
and the consciousness has just disappeared. The cause of the asphyxia 
is still undecided, many investigators holding that the centre is paralyzed 
before the terminations of the nerves in the diaphragm, while the ma- 
jority of recent investigators look upon the paralysis of those termina- 
tions as the cause of death. 

A curious change has been observed by Giirber in the Blood Cells of 
frogs poisoned with coniine. Numerous small vacuoles appear in the 
red corpuscles, and persist long after the frog shows no further symp- 
toms of poisoning. The nucleus is also somewhat altered, but not so 
characteristically. 

Coniine is rapidly excreted in the urine, so that its action passes off 
very soon even when quite large doses are taken. The treatment of 
coniine poisoning therefore consists in evacuation of the stomach and 
artificial respiration. 

Piperidine acts in the same way as coniine, but more weakly, while 
methyl- and ethyl-piperidine stand between them in toxicity. Many 
of the piperidine alkaloids cause the formation of vacuoles in the red 
blood cells of the frog, and the simpler members of the series act more 
strongly in this direction than the more complex ones, while they are 
much less active as general poisons. 

Pyridine resembles piperidine in most features but does not paralyze 
the ganglia nor increase the blood-pressure. It seems more poisonous 
in frogs, and induces distinct depression of the central nervous system, 
but like piperidine it is only feebly poisonous in mammals. Pyridine 
is excreted in the urine as methyl-pyridine, a combination between it 
and the alkyl occurring in the tissues. A similar synthesis occurs 
between methyl and telluric acid (see Tellurium). 

Quinoline and isoquinoline cause in mammals a condition of col- 
lapse similar to that seen under the antipyretics and the benzol com- 
pounds. 

Preparations. 

Conium (U. S. P.), Conii Fructus (B. P.), the dried, full-grown, unripe 
fruit of Conium maculatum, or hemlock. 

Extractum Conii (U. S. P.), 0.05-0.1 G. (1-2 grs.). 

Extractum Conii Fluidum (IT. S. P.), 0.1-0.5 c.c. (2-8 mins.). 

Tinctura Conii (B. P.), J-l fl. dr. 

Conii Folia (B. P.), the fresh leaves and young branches of Conium mac- 
ulatum, collected when the fruit begins to form. 

Succus Conii (B. P.), juice of hemlock, in which one part of alcohol is 
added to three of the juice, 1-2 fl. drs. 

Unguentum Conii (B. P.). 



QELSEMIUM. 265 

Therapeutic Uses. — Conium has passed into almost complete disuse. 
It has been prescribed in whooping-cough and chorea with doubtful 
results, and has been employed locally and given internally to relieve 
pain. Tetanus and strychnine poisoning have been treated with it 
without apparent results. 

Bibliography. 

Guttmann. Berl. klin. Woch., 1866, p. 45. 

Kolliker. Vircho w' s Arch. , x. , p. 235. 

Prevost. Arch, de Physiol. (2), vii., p. 40. 

JSoehm. Arch. f. exp. Path. u. Pharm., xv., p. 432. 

Burmeister. Inaug. Diss., Kiel, 1891. 

Gilrber. Arch. f. Anat. und Phys., 1890, p. 401. 

Cushny. Journ. of Exp. Med., i., p. 202. 

Moore and Bow. Journ. of Phys., xxii., p. 273. 

Stockman. Journ. of Phys., xv., p. 245. 

Brunton and Tunnicliffe. Ibid. , xvii. , p. 272. 

Heinz. Virchow's Arch., cxxii., p. 116. 

His. Arch. f. exp. Path. u. Pharm., xxii., p. 253. 

Cohn. Zts. f. phys. Chem., xviii., p. 112; xx., p. 210. 

Gelsemium. 

Gelsemium sempervirens (Yellow Jasmine or Carolina Jasmine) 
contains two alkaloids, Gelsemine and Gelseminine. 1 Gelsemine forms 
crystalline salts, while gelseminine is entirely amorphous, and, as far as 
is known, does not form any crystalline combinations. Gelsemine is 
only slightly active, inducing the same symptoms in frogs as strych- 
nine, but having no effects on mammals, even when injected into a vein 
in very large quantity. Gelseminine, on the other hand, is a powerful 
poison which resembles coniine in most of its effects. The action of 
the crude preparations of gelsemium is undoubtedly due to gelsemi- 
nine and not to gelsemine, as far as mammals are concerned. Large 
quantities of the extract injected into frogs may, however, increase 
the reflex movements somewhat from the gelsemine they contain. 

Action. — The symptoms of gelsemium poisoning resemble those of 
coniine so closely that the reader may be referred to the description 
given under the latter. Gelseminine differs from coniine chiefly in 
possessing a more depressant action on the central nervous system. In 
the frog the spinal cord is distinctly less active than usual before the 
ends of the motor nerves are paralyzed, and, in fact, the depression of 
the central nervous system seems to be the cause of the general 
paralysis in these animals, rather than the peripheral action, although 
this is always present, In mammals the symptoms resemble those 
of coniine more closely than in the frog, and there may be some ques- 
tion as to whether the effects are mainly central or peripheral in ori- 
gin. There is a general consensus of opinion, however, amongst those 
who have worked on the subject, that gelseminine proves fatal by para- 
lyzing the respiratory centre rather than the terminations of the nerves 
in the diaphragm and other muscles, while most writers now consider 
the asphyxia of coniine poisoning due to the peripheral action. The 

Gelsemine is frequently known as gelseminine, a use of the term which leads to some 
confusion and which is not based on the history of the drug. 



266 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

symptoms are practically identical, however, and it will probably be 
found that both act on the same points in the innervation of the 
respiration. In the meantime the question must remain undecided 
for both poisons. 

The pupil is very widely dilated by gelseminine when a solution is 
applied locally to the eye, much less so in general poisoning, in which 
the respiration generally fails before the pupil is fully dilated. The 
power of accommodation is also entirely lost when gelseminine or gel- 
semium tincture is applied to the eye. This mydriatic effect has not 
been explained, but the most plausible suggestion would seem to be 
that gelseminine paralyzes the terminations of the oculomotor nerve in 
the eye in the same way as atropine. Gelseminine differs from atro- 
pine in its behavior to other nerves, however, for although it paralyzes 
the inhibitory cardiac fibres, it does so through acting on the ganglionic 
structures on their course and not on the extreme terminations. Its 
action on the ganglia, as far as it is known, resembles that of coniine, 
but it does not cause any increase in the arterial tension, such as is 
observed under this poison. 

Preparations. 

Gelsemium (U. S. P.), Grelsemii Radix (B. P.), the dried rhizome and 
roots of Gelsemium sempervirens or nitidum. 

Extractum Gelsemii Fluidum (U. S. P.), 0.3-0.6 c.c. (5-10 mins.). 

Tinctura Gelsemii (U. S. P., B. P.), 0.3-1 c.c. (5-15 mins.). 

" Gelsemine " is an unofficial mixture of the alkaloids in very varying pro- 
portions. In some preparations no gelseminine whatever was found. 

Therapeutic Uses. — The tincture of gelsemium has been employed as 
a mydriatic in ophthalmology, but it presents no advantages over the 
more generally used preparations of atropine, and sometimes causes 
some pain and redness, which has prevented its general adoption for 
this purpose. In certain forms of neuralgia, especially of the facial 
branches of the trigeminus, gelsemium has proved of some value, when 
administered internally as the tincture. 

Bibliography. 

Ringer and Murrell. Lancet, 1876, i., p. 82. 

Putzeys and Romiee. Memoire sur 1' action physiologique de la Gelsemine. Bruxelle, 
1878. 

Cushny. Arch. f. exp. Path. u. Pharm., xxxi., p. 49. 

Sparteine. 

Another alkaloid which resembles coniine closely in its action is 
Sparteine, which is found in the common broom plant (Spartium or 
Cytisus scoparius), along with a neutral substance, Scoparin. Spar- 
teine is a pyridine derivative possessing the formula C 15 H 26 N 2 , and 
is a fluid, but forms crystalline salts, which are often prescribed instead 
of the crude preparations. 

Action. — The general effects of sparteine are almost identical with 
those of coniine, but it seems very probable that the central nervous 



SPARTEINE. 267 

system is little affected by it, the whole of the phenomena pointing to 
a paralysis of the peripheral terminations of the motor nerves and 
probably of the terminations around the cells of the sympathetic gan- 
glia. Sparteine has more effect than coniine on the heart, which it 
depresses so that the rhythm is slow and the contractions weak. 
When injected into a vein, sparteine induces less increase in the arterial 
tension than coniine, probably because the contraction of the vessels 
is counterbalanced by the weakness of the heart. No increase in the 
arterial tension is observed from the administration of sparteine inter- 
nally, and even the slight rise of pressure induced by intravenous in- 
jection is of only short duration. 

The slow pulse and slight rise of pressure observed in experiments 
in animals when sparteine is injected intravenously, have led some 
writers to ascribe to it an action similar to that of digitalis, and at 
one time sparteine was used to some extent as a substitute for the 
latter ; both experimental and clinical observations, however, go to 
show that these claims are quite unfounded, and sparteine is compara- 
tively little used at the present time, and possesses no properties which 
are likely to reinstate it in favor. 

Sparteine is very much less poisonous than either coniine or gelsemi- 
nine. It proves fatal to animals by paralyzing the terminations of the 
phrenic nerves in the diaphragm. 

Broom tops have long enjoyed a certain reputation as a diuretic, and 
this perhaps strengthened the belief in the virtues of sparteine as a 
heart remedy. The diuresis is not due to the sparteine, however, 
but to the scoparin, which seems to act on the renal epithelium in the 
same way as ITva-ursi and other remedies of that series. The broom 
tops are generally administered in the form of a decoction or infusion, 
and the large amount of water taken along with them may also tend 
to increase the urine and to strengthen the reputation of the remedy. 

Preparations. 

Scoparius (U. S. P.), Scoparii Cacumina (B. P.), the tops of Cytisus sco- 
parius or broom. 

Extractum Scoparii Fluidum (U. S. P.), 1-4 c.c. (15-60 mins.). 

Infusum Scoparii (B. P.), 1-2 fl. oz. 

Succus Scoparii (B. P.), 1-2 fl. drs. 

Sparteine Sulphas (U. S. P.) (C ]5 H 26 N 2 H 2 SO, -f 4H 2 0), colorless, white 
crystals with a saline bitter taste, very soluble in water and alcohol. The 
dose recommended by different clinicians as of benefit in heart disease varies 
from 0.004-0.8 G. (t—12 grs.) in the course of 24 hours. It may be given in 
doses of 0.1 G. (2 grs.) with perfect safety. 

Uses. — Broom tops are used as a feeble diuretic, generally in the 
form of a decoction (16 G. in 250 c.c. of water or J oz. in a half pint 
in divided doses in 24 hours), or infusion (B. P.). Sparteine has been 
advised in heart disease, but is of no value here. It has also been 
proposed to paralyze the terminations of the vagus with it before 
the administration of chloroform, the object being to avoid the reflex 
syncope, but if this were to be dreaded, a small dose of atropine would 



268 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

be preferable to sparteine. It has also been suggested as a local anaes- 
thetic in ophthalmology, but has only a feeble action. 

Bibliography. 

Fick. Arch. f. exp. Path. u. Pharm., i., p. 397. 

Masius. Bull, de l'Acad. Koy. de Med. de Beige, 1887. 

Cushny and Matthews. Arch. f. exp. Path. u. Pharm., xxxv., p. 129. 

XI. NICOTINE. 

Nicotine, the well-known alkaloid of tobacco (Nicotiana tabacum), is 
a volatile fluid, possessing a strong alkaline reaction, and forming salts 
with acids, most of which are amorphous. The exact structure of the 
nicotine molecule (C 10 H 14 N 2 ) is still under discussion. It was formerly 
supposed to be a combination of pyridine with piperidine, but a num- 
ber of its reactions seem to preclude this, and it has thus been recently 
stated to contain a pyridine and a hydrated pyrrhol ring. According 
to this theory its structural formula is probably 



CH AX/™* 

He' Jen 

N 

Another alkaloid which is practically identical with nicotine in its 
pharmacological action, is Piturine (C 12 H 16 N 2 ), which is derived from 
the pituri plant (Duboisia Hopwoodii). The leaves of the pituri are 
said to be used by the Australian natives in the same way as tobacco 
by the civilized races. 

Nicotine is the only constituent of tobacco which possesses any 
toxicological interest, although several other alkaloids are present in 
comparatively small amounts. It is accompanied by a volatile oil in 
dried tobacco, but this is only developed during the processes of pre- 
paration and seems to have no action apart from that of the other vola- 
tile oils. The odor and flavor, and probably the " strength," of to- 
bacco depends in part upon the quantity and quality of this oil, in part 
on some products of the decomposition of nicotine. Absolutely pure 
nicotine has comparatively little odor, but it decomposes when kept, 
becomes dark colored and acquires the characteristic odor of tobacco. 

Tobacco is not used in therapeutics, but is of great hygienic im- 
portance, and nicotine possesses considerable biological interest from 
the results obtained by Langley by its use in physiology in recent 
years. It acts chiefly on the central nervous system, the sympathetic 
ganglia, and the terminations of the motor nerves. 

Symptoms. — Poisonous doses administered to man or other mammals 
cause a hot, burning sensation in the mouth, which spreads down the 
cesophagus to the stomach, and is followed by salivation, nausea, vom- 



NICOTINE. 



209 



Fig. 24. 



itiug and sometimes purging. The breathing is quick, deep and 
labored, and is often accompanied by moist rales. The pulse is gen- 
erally slow and somewhat weak at first and then becomes very rapid, 
but after very large doses may be first accelerated and then slow and 
feeble. Some mental confusion, great muscular weakness, giddiness and 
restlessness are followed by loss of coordinating power and partial or 
complete unconsciousness. 
Clonic convulsions set in 
later, accompanied by fibril- 
lary twitching of various 
muscles, and eventually a 
tetanic spasm closes the 
scene by arresting the res- 
piration. In other instances 
the convulsions are followed 
by complete relaxation of 
all parts of the body, the 
reflexes disappear, the res- 
piration becomes slow and 
weak and finally ceases, the 
heart continuing to beat 
for some time afterwards. 
Very large doses of nico- 
tine may prove fatal within 
a few seconds ; the symp- 
toms are those of sudden 
paralysis of the central 
nervous system including 
the respiratory centre, and 
no convulsions are de- 
veloped. 

In the frog the same ex- 
citement and violent convul- 
sions are seen as in mam- 
mals, but the respiration 

SOOn Ceases, and there fol- . Diagram of the regulating nerves of the heart. P, inhib- 

7 . ltorv fibres arising m the vagus centre in the medulla ob- 

10WS a "cataleptic Stage longata and terminating around ganglion cells in the auricle 

i . t .! • l M). The axis cvlinders issuing from these cells terminate 

in Which the animal assumes on the muscular fibres of the auricle and ventricle ( V). R, 

i , • , • , , • , -i accelerator fibres issuing from the spinal cord and termi- 

a cnaraCteriStlC attltUCle. mating around ganglion cells in the stellate ganglion'/. The 

Thp fnrp W«; nrp prnc^prl in axis fibres of these ganglion cells run through the Annulus 

X1IC J-ulc -itgs tiic oiusoeu in Vieussenii and terminate on the muscular fibres of the auri- 

froilt Of the Sternum, and de and ventricle N, N 1 points at wMch ««»*. comim 

J curartne, etc., act— the ganglion cells surrounded nj tne 

are riffid the thighs are at terminations of the nerves. 3f, points at which muscarine 

. , & ' & . ' and atropine act— the terminations of the fibres which arise 

right angles to the axis 01 from the intra-cardiac ganglia. 

the body and the legs are 

flexed on them but are not rigid. When a leg is drawn down it at 
once returns to its original position, and the frog still attempts to 
escape when it is aroused. Fibrillary contractions arc observed in 
many of the muscles. Somewhat later, the reflexes disappear, the 




270 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

muscles become flaccid, and eventually complete paralysis occurs from 
a curara-like action on the terminations of the nerves. 

Nicotine has but little toxic action on the lowest invertebrates, but 
as the nervous system begins to be differentiated it causes paralysis, 
and still higher in the scale the paralytic action is preceded by a stage 
of stimulation. 

Circulation. — The action on the circulation is extremely complex, 
as a number of factors are involved. After moderate quantities the 
heart is slow and may stand still in diastole for a few seconds, but then 
recovers gradually and regains its former rhythm or becomes somewhat 
quicker. The slow pulse is due to stimulation of the ganglia on the 
vagus nerve (Fig. 24, N), exactly the same effects being produced as 
by stimulation of the vagus fibres in the neck. It is not affected by 
section of the cervical pneumogastric, as the path from the ganglia to 
the cardiac muscle fibres is still intact, but on the other hand, it is pre- 
vented by atropine, which acts on the extreme terminations of the in- 
hibitory fibres, and therefore blocks the passages of impulses from the 
ganglia to the muscle. It is also prevented by a number of drugs, such 
as curara and coniine, which paralyze the ganglia. 

This stimulation of the ganglia is of but short duration, soon passing 
into paralysis, which obstructs the passage of the inhibitory impulses 
from above. On stimulating the vagus after nicotine there is conse- 
quently no slowing of the heart but often some acceleration, due to the 
fact that the accelerating fibres running along with the inhibitory in 
the vagus nerve have no ganglionic apparatus in the heart, and are 
therefore unaffected by nicotine. Although inhibitory impulses can 
no longer reach the heart from above, the intracardiac inhibitory 
neuron is still intact, and stimulation of the venous sinus in the frog 
still causes arrest of the heart exactly as in the normal animal. The 
stimulating current here reaches the inhibitory nerves beyond the 
paralyzed ganglia (Fig. 24, X), and these preserve their usual irrita- 
bility. In the same way a number of poisons which act upon 
the extreme terminations of the inhibitory fibres in the heart muscle 
(Fig. 24, M) can slow the rhythm even after the ganglia have been 
paralyzed by nicotine (see the Pilocarpine and Muscarine group). The 
results of the stimulation and subsequent paralysis of the ganglionic 
structures on the inhibitory fibres by nicotine are the preliminary slow- 
ing and subsequent slight acceleration of the heart rhythm seen in both 
cold- and warm-blooded animals In larger doses nicotine produces 
no slowing of the heart, owing to the ganglia being paralyzed imme- 
diately, without previous stimulation. 

In addition to its action on the peripheral inhibitory ganglia, nico- 
tine seems to stimulate the vagus centre in the medulla, as the slow- 
ing is greater when the vagi are intact than when they are divided. 
But apart from this action on the inhibitory apparatus, nicotine pos- 
sesses some direct action on the heart muscle, which appears to be first 
stimulated and then depressed. Accordingly, when the inhibitory appa- 
ratus has been previously paralyzed, moderate quantities increase the 



NICOTINE. 271 

rate of the heart beat considerably, while very large ones slow and 
weaken it. It has been supposed that this quickening is due to action 
on the accelerator centre, or on the ganglia on the course of the sym- 
pathetic accelerator fibres (N' 9 Fig. 24), but this seems not to be the 
only cause, for Wertheimer found the acceleration continue even after 
extirpation of these ganglia. The quickening must be attributed 
in part, or wholly to action on the cardiac muscle, or on the termina- 
tions of the accelerator nerves in it. The subsequent slowing and weak- 
ness is undoubtedly due to a paralyzing action on the muscle itself. 

On the injection of nicotine into a vein or subcutaneously an im- 
mense augmentation of the arterial tension occurs ; this may be due 
in part to stimulation of the vaso-constrictor centre in the medulla, but 
is to be ascribed chiefly to peripheral influences, for it has been ob- 
served after section and even after total removal of the spinal cord. 
The vaso-constrictor nerves pass through ganglia on their way to the 
vessels and the rise of the blood-pressure seems to be mainly caused 
by a stimulation of these ganglia. 

The constriction of the vessels can be observed in many parts of the body 
— mesentery, foot, rabbit's ear, etc. In these parts the pallor produced by 
the narrowing of the vessels is followed by redness and congestion owing to 
the paralysis of the ganglia, and at the same time the pressure falls to a 
level somewhat below the normal. In some parts of the body no constric- 
tion of the vessels occurs ; for example, the dog's lip and mouth are con- 
gested first and then become pale. This flushing seems partly due to the 
stimulation of the ganglionic apparatus on the vaso-dilator fibres for these 
parts, but cannot be wholly explained thus, for it occurs also after removal 
of the superior cervical ganglion, although to a less marked degree. It may 
therefore be caused in part by direct action on the vessels. 

After a few minutes the blood-pressure falls to the normal level or 
lower, but a second injection again produces a similar rise in the arterial 
tension, unless the first was large enough to paralyze the ganglia. 
Eventually nicotine lowers the blood-pressure owing to the weakening 
action on the heart. 

• Respiration. — The respiration is at first rapid and shallow with some 
deficiency in the expiratory movements, but after a time, while main- 
taining the acceleration, it becomes deeper. It is liable to be interrupted 
at this stage by the convulsions, but if these do not prove fatal, it 
gradually becomes slower while remaining deep. Later, pauses in the 
position of expiration appear, and the movements become weaker until 
they disappear, the animal dying of asphyxia. The rapid, shallow 
movements in the beginning of the intoxication are absent in animals 
in which the pneumogastric nerves have been previously divided, so 
that this phenomenon appears to be due to the alkaloid acting as an 
irritant to the pulmonary branches of the pneumogastric. The later 
features are caused by its acting on the respiratory centre directly, first 
stimulating and then paralyzing it. After large doses this direct action 
alone may be elicited. The paralysis of the respiration is the cause 
of death, the heart continuing to beat for some time afterwards al- 
though slowly and weakly. 



272 



ORGANIC DRUGS ACTING AFTER ABSORPTION. 



Fig. 25. 



Most of the Secretions are increased temporarily by nicotine. The 
glands investigated have generally been the salivary, where it is found 
that the secretion is increased by the injection of small quantities, but 

is afterwards depressed, while large 
doses diminish it at once. The seat 
of action is again the ganglionic ap- 
paratus on the secretory nerves. If 
the chorda tympani be stimulated in 
the normal animal a large secretion 
of saliva at one follows, but if a 
sufficient quantity of nicotine be in- 
jected no such effect follows its 
stimulation. If, however, the nerve 
fibres be stimulated between the 
ganglion cells and the gland (at 
X in Fig. 25), the secretion again fol- 
lows as before. On the other hand, 
nicotine increases the secretion whether 
the chorda be intact or not, but ceases 
to act if the connection between the 
ganglion cells and the gland be inter- 
rupted. These results can only be in- 
terpreted by nicotine first stimulating 
and then paralyzing the ganglia on the 
course of the chorda tympani. In the 
same way it first stimulates and then 
paralyzes the ganglia which lie in the 
course of the sympathetic salivary 
fibres. Pilocarpine and muscarine 
cause profuse salivation after nicotine, 
because they stimulate the terminations 
of the nerves in the gland cells, and it 
is therefore immaterial whether the 
connection with the central nervous 
system be interrupted or not. On the 
other hand, the reflex secretion of saliva 
normally produced by irritation of the 
mouth or by chewing is prevented by 
nicotine. Atropine stops the secretion 
produced by nicotine by paralyzing the 
extreme terminations of the nerves. 

The other secretory glands are affec- 
ted in the same way by nicotine, and 
although the details have not been 
worked out so carefully as for the sali- 
vary glands, there is no question that their secretions are first in- 
creased by the stimulation of the ganglia on the course of their 
secretory nerves, and then lessened by their paralysis. Thus the 




Diagram of the innervation cf the sub- 
maxillary gland. P, a fibre of the chorda 
tympani issuing from the pons Varolii 
and after a devious course terminating 
around a ganglion cell in the hilus of the 
submaxillary gland. The axis from this 
ganglion cell runs to the secretory epi- 
thelium. R, a fibre issuing from the spinal 
cord aud after running through the sym- 
pathetic chain in the neck, terminating 
around a ganglion cell in the superior cer- 
vical ganglion G. The axis from this cell 
runs to the secretory epithelium. In the 
diagram the nerves are represented as 
running to separate acini. N, N', gang- 
lion cells surrounded by the termina- 
tions of the nerves — the points at which 
nicotine acts. M, the terminations of the 
secretory fibres connected with the chorda 
tympani — the points at which atropine, 
muscarine, and pilocarpine act. 



NICOTINE. 273 

sweat secretion is found to be markedly increased, as also the 
secretion of the bronchial mucous glands. The urine and bile have 
not been shown to be affected by nicotine, and as their secretion does 
not seem to be so dependent upon nervous influences, it is probable 
that it is but little changed in amount. 

Nicotine produces extreme Nausea and Vomiting when taken even 
in comparatively small quantities, a fact which is generally recognized 
by tyros in smoking. This may be in part central in origin, but is 
mainly due to the powerful contractions of the stomach walls. This 
contraction extends throughout the intestinal tract, so that repeated 
Evacuation of the Bowel occurs. Eventually a tetanic contraction of 
the whole intestine sets in, the lumen being much narrowed, or even 
entirely obliterated. 1 During this tetanic stage there is no peristaltic 
movement, but afterwards the wave contractions set in again in much 
exaggerated form. The mesenteric vessels are narrowed during the 
tetanic period so that the bowel is pale and anaemic, but when peri- 
stalsis recommences they seem more congested than usual. Salvioli 
has shown that very similar effects are to be observed in the excised 
intestine when blood containing nicotine is perfused through its vessels, 
so that the increased movements are due to action on the structures 
of the wall of the bowel. Atropine prevents the peristalsis caused by 
nicotine, so that on the analogy of the action of these drugs on the 
secretory glands and on the heart it seems probable that nicotine 
stimulates the ganglionic apparatus in the wall of the intestine. The 
constriction of the vessels may be due to action on the ganglia of the 
coeliac plexus. 

Similar movements are produced by nicotine in the bladder and 
uterus, both of which are thrown into tetanic contraction. The urine 
is therefore expelled very soon after the injection of nicotine, and this 
probably gave rise to the erroneous view that the renal secretion was 
increased. 

The action of nicotine on the Pupil varies in different animals, for 
while in the cat and dog its application either intravenously or locally 
produces marked but transitory dilation, in the rabbit partial con- 
striction sets in immediately. In cases of acute poisoning in man con- 
traction is generally seen at first and is followed by dilatation. In 
birds nicotine causes very marked contraction of the pupil, apparently 
owing to direct action on the muscles of the iris. The size of the pupil 
is regulated by two sets of nerves, the motor oculi and the sympathetic, 
and the ciliary fibres of both of these are interrupted by ganglia in 
their passage from the brain to the iris, those of the motor oculi by the 
ciliary ganglion, those of the sympathetic by the superior cervical 
ganglion (see Fig. 26, p. 287) ; the varying effects of nicotine may 
be due to its stimulating the one ganglion more strongly in one species 

^ayliss and Starling (Jour, of Phys., xxiv., p. 13S) observed inhibition of the 
intestinal movements induced in dogs whose vagi and splanchnic nerves had been di- 
vided previously and ascribe it to an intense stimulation of the peripheral splanchnic 
apparatus. At the same time the pneumogastric fibres cease to have any control over 
the intestinal movements. 
18 



274 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

of animals, the other in another. It is found, however, that atro- 
pine does not remove the effects of nicotine on the rabbit's eye, which 
would seem to indicate an action on the muscular fibres of the iris. 
Several other effects on the orbital muscles are seen ; thus in cats 
and dogs the nictitating membrane is withdrawn, the eye opens and is 
directed forwards, while in the rabbit these symptoms arc preceded by 
a stage in which the nictitating membrane is spread over the cornea 
and the eye is tightly closed. These are probably produced by action 
on the superior cervical ganglion. 

Nicotine, then, first stimulates and later paralyzes all the Sympa- 
thetic Ganglia, whether applied locally to them or injected into the cir- 
culation. In these ganglia, the characteristic formation is the basket- 
like arrangement of the terminations of the entering nerve, which 
surround a large nerve cell from which an axis cylinder runs to the 
muscle or secretory cell. A nerve impulse from the central nervous 
system passes from the basket to the cell and thence to the periphery] 
Langley has recently shown that small quantities of nicotine stimulate 
the cell of the peripheral neuron, for the same effect is obtained from 
the application of the poison to the ganglion whether the basket-like 
terminations round the cell are normal or have degenerated. This 
renders it probable that the paralysis of the ganglia observed from 
larger quantities of nicotine is also due to action on the cell and not on 
the terminations. 

In the frog nicotine produces fibrillary contraction of the muscles, 
which is not prevented by previous division of the nerves leading to 
them, but disappears on the injection of curara. The phenomenon is 
therefore independent of the central nervous system ; and it is not pro- 
duced by muscular changes, for in this case it would persist after cur- 
ara ; it must consequently be due to stimulation of the terminations of 
the motor nerves. These terminations are subsequently paralyzed if 
the quantity injected be large enough. In mammals the twitching of 
the muscles is prevented by section of the nerves, and is, therefore, due 
to central action, but large quantities of nicotine cause paralysis of the 
nerve ends exactly like curara. The nerves of the orbital muscles are 
found to be paralyzed sooner than those of the rest of the body. 

Nicotine does not seem to act on Muscular Tissue in general, 
although some obscure symptoms have been ascribed to changes in the 
cardiac and iris muscle. 

The convulsions seen in both cold- and warm-blooded animals evi- 
dence the influence of nicotine on the Central Nervous System. The 
spinal cord is thrown into a condition of exaggerated irritability, and 
the reflexes are correspondingly increased, but the convulsions do not 
seem to be due so much to the spinal cord as to the medulla oblongata 
and hind brain, for they are not tonic but clonic in character, and are 
much weaker after division of the cord immediately below the medulla 
than in the intact animal. The medullary stimulation also betrays 
itself in the rapid and deep respiration, and is perhaps in part respon- 
sible for the inhibitory slowing of the heart and the rise in the blood- 



NICOTINE. 275 

pressure. The higher centres in the brain seem to participate but 
little in the stimulant action of nicotine, which is short-lived, and 
soon gives way to marked depression of the whole central nervous 
system, manifested in the slow respiration, the low blood-pressure, the 
disappearance of the reflex movements and the final unconsciousness. 

The Excretion of nicotine is probably carried on mainly by the 
kidneys, for it is found in the urine very soon after it enters the blood. 
It has also been detected in the saliva and perspiration. It has been 
shown repeatedly that nicotine and some other alkaloids are weakened 
in toxic effect or rendered entirely inactive by being mixed with an 
extract of the liver or of the suprarenal capsules ; but no satisfactory 
explanation is forthcoming, though there is every reason to suppose 
that much of the nicotine absorbed from the stomach and intestine is 
thus modified in its passage through the liver. 

When small quantities of nicotine are injected repeatedly, the body 
soon gains a certain Tolerance, and no symptoms whatever are pro- 
duced by doses which would in ordinary cases produce grave poison- 
ing. A familiar example of this tolerance is seen in the practice of 
smoking. The first use of tobacco is in the great majority of indi- 
viduals followed by vomiting and depression which may even amount 
to collapse, but after a few experiences no symptoms follow smoking, 
owing to the cells of the body becoming tolerant of the poison. In 
some individuals no such tolerance is developed, however, and each at- 
tempt to acquire the art of smoking or chewing tobacco is followed by 
the same symptoms. In animal experiments it is often found that 
while one application of nicotine produces considerable ganglionic 
stimulation, the second has much less effect. This is probably due 
not to the establishment of tolerance, but to the first dose having 
produced primary stimulation and then depression of the ganglia, this 
depression, while not amounting to complete paralysis, being sufficient 
to counteract to some extent the stimulant action of the second injection. 

An effect of an entirely different character has been found to follow 
the successive application of large doses. If a quantity just smaller 
than the lethal one be injected into an animal, and two or three 
days after its recovery a second injection of the same amount be 
made, death will follow, but some of the symptoms, such as the con- 
vulsions > may be entirely absent. The reason for the fatal effect is 
believed to be the lasting depression of the heart in the frog, and of 
the respiratory centre in mammals. The absence of the convulsive 
seizures is said by von Anrep to be due to a similar depression of the 
gray matter of the spinal cord and medulla. Large quantities of nico- 
tine are, therefore, cumulative in their action, while smaller quantities 
lead to a condition of tolerance. 

Xicotine and Piturine are not used in therapeutics. Tobacco was 
formerly employed iu the reduction of intestinal hernia, and for this 
purpose was injected into the rectum in the form of an infusion. Sev- 
eral cases of poisoning and the introduction of general anaesthesia led 
to its disuse. 



276 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

Tobacco. 

Tobacco had been in use among the aboriginal tribes of America 
before they became known to civilization. It was introduced into 
Europe soon after the discovery of America, and its use as an article 
of luxury, beginning in England, soon spread to the continent, and in 
spite of papal bulls and numerous efforts on the part of the secular 
authorities, has continued to enthral a considerable portion of the 
human race. The most widespread use of tobacco — smoking — is also 
the most ancient one, having been that of the aboriginal Indians. 
Snuff-taking, introduced by Francis II. of France, remained fashion- 
able for a long time, but is now almost obsolete. Tobacco-chewing 
is a more modern development, but shows no signs of abatement. 
Curiously enough, the leaves of the pituri plant, which, as has been 
mentioned, contain an alkaloid nearly allied to nicotine, are formed 
into a mass and chewed by the natives of Australia. In smoking, 
snuffing or chewing, nicotine is absorbed. It has been stated and the 
statement has received an undeservedly wide circulation, that tobacco 
smoke contains no nicotine but merely the products of its decomposi- 
tion ; but as a matter of fact, tobacco smoke, whether from cigars or 
pipes, contains a certain amount of the alkaloid itself, along with pyri- 
dine and many of its compounds. The amount of nicotine in tobacco 
smoke cannot be definitely stated, as it depends on the kind of tobacco, 
as well as on the way in which it is inhaled ; but only a small propor- 
tion of that contained in tobacco passes over in the smoke. In snuff 
the nicotine is generally small in amount, while in chewing tobacco 
there is generally a varying amount of foreign matter, such as molasses. 
The enjoyment derived from the use of tobacco has never been ex- 
plained, and it is not even proved that nicotine is essential to the 
pleasurable results ; consideration of the pharmacological effects of 
nicotine gives no clue, for these are of the opposite nature. It has 
been suggested that smoking gives repose and thereby improves intel- 
lectual work, but this is denied by many habitual smokers. It has 
also been stated and denied that the mental energy is reduced by the 
use of tobacco, and an attempt has been made to demonstrate this by 
measuring the amount of work done with and without tobacco ; but 
investigators are not agreed on the results, which probably depend 
largely upon the individual. One fact is certain, that the tobacco habit 
cannot be compared Avith the use of such drugs as morphine, cocaine, 
or alcohol, for it is not taken with the purpose of producing stimulation 
or depression of the central nervous system, and it seems doubtful 
whether the nicotine ordinarily absorbed really has any action whatso- 
ever. Perhaps the local effects on the mouth, nose and throat play a 
larger part in the effects of tobacco than is generally recognized. A 
certain amount of rhythmic movement demanding no exertion seems 
in itself to have a soothing, pleasure-giving effect, for it is otherwise 
impossible to explain the satisfaction enjoyed by many in chewing 
tasteless objects, such as gum or straws. A curious fact which tends 



NICOTINE. 277 

to show that tobacco smoking is not carried on for the sake of the 
nicotine absorbed is that the pleasure derived from a pipe or cigar is 
abolished for many persons if the smoke is not seen, as when it is 
smoked in the dark. 

Most people may indulge in the moderate use of tobacco for many 
years with perfect impunity, but its excessive use is followed in many 
individuals by a number of symptoms, some of them trivial, others 
indicating grave changes in important organs. 

One of the commonest effects of overindulgence in tobacco is a chronic 
inflammation of the throat and upper parts of the respiratory passages, 
leading to hoarseness and excessive secretion of the mucous glands. 
This is explained by the constant application to the throat of an irri- 
tant, alkaline vapor, and is probably not due to the specific action of 
nicotine. A similar irritated condition of the tongue is frequently met 
with, more especially when the hot vapor is directed especially on one 
part, as in pipe smoking, and it is sometimes stated that the constant 
irritation thus produced renders the tongue and lip more liable to can- 
cerous disease. Dyspepsia, want of appetite, and consequent loss of 
flesh may also be explained by the local irritation produced by the 
nicotine swallowed in the saliva. A common result of the abuse of 
tobacco is palpitation and irregularity of the heart, which has as yet 
received no explanation. Another important symptom is dimness of 
vision, especially for colors, and imperfect accommodation of the lens 
for distance, which may go on to complete blindness in one or both 
eyes. In early cases the retina often appears pale, and if the condition 
persists, atrophy of the optic nerve may result, probably following on 
degenerative changes in the ganglion cells of the macular region of the 
retina. The hearing is said to be affected by excessive smoking, but 
the symptoms are indistinct and variable. Nervous symptoms such as 
tremor, exaggeration of the reflexes, headache and giddiness are some- 
times developed in workmen in tobacco factories, but they do not seem 
to be induced by smoking or chewing tobacco, though depression, muscu- 
lar weakness and giddiness are sometimes complained of. In the great 
majority of cases of chronic tobacco poisoning, the symptoms disappear 
on abandoning the habit, or even on restricting the daily consump- 
tion. A series of subjective and even objective symptoms are said to 
be induced in neurotic subjects by the sudden withdrawal of tobacco. 

The prolonged administration of nicotine to animals does not seem 
to produce symptoms analogous to those seen in man. Vas found in 
rabbits subjected to daily injections of nicotine for several weeks a 
great reduction of the red blood cells along with a smaller increase in 
the leucocytes. The animals lost in weight, and changes were found in 
the nerve cells of the spinal cord and sympathetic gauglia similar to 
those described under chronic alcoholic poisoning. 

Bibliography. 

Langley and Dickinson. (Journal of Physiology, xi., p. 205), give all the more im- 
portant experimental literature up to 1890. 



278 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

Langley, Langley and Sherrington, Langley and Anderson. Journal of Physiology, xii., 
xiii., xv., and xxvii., p. 224. 

Wertheimer et Colas. Archiv de Physiol. (5), iii., 1891, p. 341. 

Baldi. Arch. Ital. de Biol., xv., 1891, p. 314. 

Dornbluth. Sammlung klinischer Vortriige, No. 122. 

Vas. Arch. f. exp. Path., xxxiii., p. 141. 

Greenwood. Journal of Physiol., xi., p. 573. (Action on invertebrates.) 

Salvioli. Arch. f. Anat. und Phys., 1880, Suppl., p. 95. 

Moore and Row. Journ. of Physiol., xxii., p. 273. 

Winterberg. Arch. f. exp. Path. u. Pharm., xliii., p. 400. 

Ilabermann. Ztschr. f. physiol. Chem., xxxiii., p. 55. 

Beyer. Johns Hopkins Hospital Keports, ix., p. 111. 

Birch- Hirschf eld. Arch. f. Ophthalmologic, liii., p. 79. 



XII. LOBELINE. 

Lobeline, the alkaloid of Lobelia inflata or Indian Tobacco, is believed to 
possess the formula C lfi H 24 NO, and resembles nicotine in some respects in its 
action, but comparatively little is known regarding it. 

Lobelia generally causes violent vomiting in man, and this is commonly 
the only symptom, as the greater part of the poison is thus eliminated 
When the emesis is insufficient, however, pain in the abdomen and purging 
have been observed, followed by confusion and collapse with a small, weak 
pulse, convulsions, dyspnoea and finally asphyxia. The pupil seems to vary 
in different cases, sometimes being dilated, sometimes contracted. The 
mucous membrane of the stomach and bowel has been found in a state of 
acute inflammation in some cases of fatal poisoning. 

When injected into mammals, lobeline causes rapid, dyspnceic breathing, 
increased reflex irritability, vomiting and salivation, and finally paralysis 
of the respiration. In the frog the spontaneous movements cease soon after 
the injection, and the reflexes are then more easily elicited than usual, but 
the terminations of the motor nerves are soon paralyzed in the same way as 
by curara. 

The higher divisions of the central nervous system seem to be depressed 
in the frog, but not in the mammal, while the spinal cord and medulla 
oblongata appear stimulated in both, as is indicated by the increase in the 
reflex irritability and by the acceleration of the respiration. The vomiting is 
also ascribed to stimulation of the medullary centres. Lobeline paralyzes 
the terminations of the motor nerves in the frog, but not in the mammal. 
Its action on the ganglia is unknown, but it seems to affect the inhibitory 
apparatus of the heart in the same way as nicotine, so that the pulse is first 
slow and then returns to its former rate or may be accelerated. The blood- 
pressure is reduced at first, but soon rises above the normal height ; when 
vomiting is induced, great variations in the rate of the heart and in the 
blood-pressure attend it. The local application of lobeline to the eye is fol- 
lowed by contraction of the pupil, while in general poisoning in mammals 
Dreser observed only dilatation. The respiration is much increased in rate and 
the individual movements are deeper and stronger. The terminations of the 
vagus in the bronchial muscles or in ganglia in the lungs were found by 
Dreser to be paralyzed by lobeline, so that stimulation of that nerve no 
longer narrows the calibre of the air passages. 

Preparations. 

Lobelia (U. S. P., B. P.), the leaves and tops of Lobelia inflata, U. S. P., 
the dried herb, B. P. 

Extractum Lobelise Fluidum (U. S. P.), 0.06-0.3 c.c. (1-5 mins.). 
Tinctura Lobelise (IT. S. P.), 0.6-4 c.c. (10-60 mins.). 
Tinctura Lobelise Mtherea (B. P.), 5-15 mins. 



ATROPINE SERIES. 279 

Therapeutic Uses. — Lobelia was formerly used as an emetic, but is exceed- 
ingly depressant and unreliable, and if vomiting does not occur is liable to 
give rise to the most alarming symptoms of poisoning. The only condition 
in which it is now used at all is in " dyspnoea and asthma of nervous origin, ' ' 
i. e. , in cases of asthma in which no organic lesion can be discovered, and 
which are therefore by a dangerous inference supposed to be due to contrac- 
tion of the bronchial muscles. Its action certainly supports this use of the 
plant, but perhaps it aids in these conditions as much by the increased se- 
cretion of the mucous membranes owing to the nausea as through its action 
on the motor nerves of the bronchial muscles. Its effects must be carefully 
watched, as the preparations seem to vary in strength, and numerous alarm- 
ing symptoms and even fatal results have followed its use. 

Bibliography. 

Ott. Phil. Med. Times, iv., p. 121, 1875. 

Bonnberg. Inaug. Diss., Kostock, 1880. 

Dreser. Arch. f. exp. Path. u. Pharm., xxvi., p. 237. 



XIII. THE ATROPINE SERIES. 

The atropine series contains a number of very closely allied alka- 
loids, of which the chief are Atropine, Hyoscyamine and Hyoscine or 
Scopolamine. They are found in several plants of the Solanaceae order, 
and in most cases several of them occur together. 

Atropine may be broken up by the action of alkalies into an alka- 
loid, Tropine, and Tropic Acid. The former is a pyridine compound 
very closely allied to Ecgonine (see cocaine) as may be seen by its 
structural formula, while the latter is an aromatic acid. 

Atropine. 



Tropine radicle. Tropic acid radicle. 

CH — CH CET 

I 2 I I 2 

N(CHJ CHO - CO — CH — C C H. 



I _ 



Hyoscyamine may be decomposed in the same way, and into the same 
two constituents, and appears not only to be isomeric with atropine in 
the ordinary sense, but to differ from it only in the physical arrange- 
ment of the tropine and tropic acid radicles. This slight difference is, 
however, sufficient to alter its action somewhat. The close relationship 
subsisting between atropine and hyoscyamine is further shown by the 
fact that the latter can be very easily changed to atropine, and in fact, 
is so changed by many of the ordinary methods of extraction. 

Scopolamine (hyoscine) was formerly supposed to be another isomer 
of atropine, but has lately been shown to differ slightly in its formula, 
which is C 17 H 21 N0 4 . It is very closely allied to atropine, and is de- 
composed into tropic acid and Scopoline (Oscine), which was formerly 
supposed to be isomeric with tropine, but has been shown to differ 
from it in the number of hydrogen and oxygen atoms. 



280 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

A number of other alkaloids have been described in different plants, 
generally associated with one or more of those already mentioned. It 
is often doubtful, however, whether they are really new alkaloids 
or whether they are not merely mixtures of atropine, hyoscyamine 
and hyoscine. Their formulae are generally said to be the same as 
that of atropine, and the differences between them are often so slight 
as to suggest that a mixture of two alkaloids has been the subject of 
examination. Thus, an alkaloid, Duboisine, has been described in 
Duboisia myoporoides, but has been shown to consist at one time of 
scopolamine, at another of hyoscyamine according to the condition of 
the plant and the variety examined. Mandragorine, found in Man- 
dragora (Mandrake) appears to be closely allied to atropine, although 
it has not been subjected to careful analysis as yet. Daturine, which 
was formerly believed to be a new alkaloid, is now stated to be atropine 
or a mixture of atropine and hyoscyamine. Atropamine, a new alkaloid 
found by Hesse in some species of Belladonna, differs slightly in 
formula from atropine, from which it may be formed by the applica- 
tion of heat ; it is decomposed into a substance which is isomeric 
with tropine, but which differs from it in some respects and which has 
been called ft-tropine. Atropamine is isomeric but not identical with 
Belladonnine, which is a compound of yet another isomer of tropine, 
bellatropine. Pseudo -hyoscyamine is said to differ from atropine and 
hyoscyamine in some of its chemical relations, but has not been the 
subject of much work as yet. Atroscine is isomeric with scopolamine 
and the same relation appears to exist between them as between atro- 
pine and hyoscyamine. 

After atropine had been found to be a compound of tropine and 
tropic acid, a number of other acids were attached to tropine in the 
same way as tropic acid. These artificial alkaloids are known as Tro- 
peines, and in action resemble atropine in some points while differing 
from it in others. Further study of the action of these tropeines is 
exceedingly desirable, and promises to be of considerable value in 
practical therapeutics. The only artificial tropeine w r hich has as yet 
been used in medicine is the compound of tropeine and oxytoluic acid 
known as Homatropine. Scopoleines have been formed by substituting 
other acids for the tropic acid of scopolamine, but none of them has 
proved of value in therapeutics as yet. 

It must be understood that the combination of tropine and its allies 
with tropic acid does not partake in any way of the nature of the com- 
bination of an ordinary alkaloid, such as morphine, with an acid. The 
bond is the much closer one seen in the compound ethers, and the 
resulting substance is alkaline and combines with acids to form salts 
exactly as other alkaloids do. 

The chief plants containing these alkaloids are the following : 
Atropa Belladonna (Deadly nightshade) containing atropine mainly, 
but also varying quantities of hyoscyamine, scopolamine and sometimes 
of atropamine and belladonnine. 



ATROPINE SERIES. 281 

Hyoscyamus niger (Henbane), containing hyoscy amine and scopola- 
mine with smaller quantities of atropine. 

Datura Stramonium (Thornapple), containing atropine, hyoscy amine 
and some scopolamine. 

Of less importance are : 

Duboisia myoporoides, containing scopolamine or hyoscyamine, together 
with pseudo-hyoscyamine and other alkaloids. Another species of Duboisia 
contains piturine, an alkaloid nearly allied to nicotine. 

Scopolia atropoides, containing hyoscyamine and scopolamine and perhaps 
small quantities of atropine. 

Mandragora autumnalis, or Atropa mandragora (Mandrake), containing 
mandragorine, which is perhaps a mixture of several of the better known 
alkaloids. 

A number of other Solanacese — e. g., tobacco and potato leaves, are said 
to contain small quantities of one or other of these alkaloids but the 
quantity present here is too small to be of any importance. A ptomaine 
formed by the decomposition of fish and meat and known as ptomatropine 
also produces symptoms closely resembling those of atropine poisoning, but 
has not been isolated as yet. 

These alkaloids all resemble each other closely in the effects pro- 
duced by them in animals. Some differences in the symptoms exist, 
however, and the action of atropine alone will first be described and 
later the points in which that of hyoscyamine and of scopolamine differ 
from it. 

Atropine acts as a stimulant to the central nervous system and 
paralyzes the terminations of a number of nerves, more especially those 
that supply involuntary muscle, secretory glands and the heart. 

Symptoms. — In man and the higher animals small toxic doses cause 
dryness of the skin and throat, thirst, difficulty in swallowing and 
hoarseness in speaking. There is often nausea and in some cases 
vomiting, headache and giddiness ; the pupils are wider than normal 
and the sight may be indistinct, especially for near objects. The res- 
piration and pulse are quickened, or the latter may at first be some- 
what slowed. A symptom that is often present, though by no means 
invariably so, is redness of the skin, more especially of the head and 
neck; the conjunctiva may also be congested. After larger doses 
the same symptoms are observed, but are soon followed by others of 
graver import. The patient can no longer swallow, although suffering 
from intense thirst, the heart is generally extremely rapid, speech is 
difficult and hoarse, and the pupils are dilated until the iris almost dis- 
appears. Restlessness and garrulity point to an increase in the irri- 
tability of the brain ; the patient at first talks in a perfectly normal 
way but soon becomes confused, begins a sentence and does not finish 
it, often bursts into laughter or tears, and in short becomes delirious 
and eventually maniacal. Often marked tremor of different muscles 
may be observed, and eventually convulsions set in and may be the 
cause of death through the failure of the respiration. As a general 
rule, however, the stage of excitement passes into one of depression, 
the patient sinks into a sleep, which deepens into stupor and coma, 



282 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

the respiration and heart become slow, weak and irregular, and death 
eventually occurs from asphyxia. 

In the frog the injection of small quantities of atropine is followed by 
a stage of increased reflex excitability, exactly resembling that seen under 
strychnine. It is generally of short duration, however, and is followed 
by a stage in which the frog lies motionless and does not react to stim- 
ulation in any way. After a variable time, sometimes a few hours, 
oftener several days, a return of the first symptom occurs, the reflex 
being much exaggerated and the tonic convulsions described under 
strychnine being generally developed. This stage slowly passes off 
and the animal again becomes normal. 

Action. — These symptoms both in mammals and amphibians indi- 
cate stimulation of the Central Nervous System followed by depression. 
Those observed in man sometimes resemble those seen in the excite- 
ment stage of alcoholic poisoning, and it has been suggested that in 
both the cause is rather a lessening of the control normally exercised 
by the higher powers over the lower motor areas than a true stimula- 
tion of the latter. But this is shown to be incorrect by the fact 
that in atropine poisoning the motor area is more easily stimulated 
by the electric current than normally. The stimulant action of atro- 
pine is also seen in the increased reflex response to irritation of the 
skin, as well as in the augmented activity of the centres in the medulla. 
The nervous symptoms under atropine, therefore, arise from true stim- 
ulation of the central nervous system, but they are wholly different 
from those produced by strychnine, because the latter acts more espe- 
cially on the lower parts of the nervous axis, while atropine acts more 
strongly on the higher divisions. The most marked symptoms of 
strychnine poisoning arise from the spinal cord and medulla oblongata, 
and consist in increased reflex movements and convulsions, while 
those caused by atropine are rather to be referred to the brain, and 
consist in increased coordinated movements, such as talking and 
delirium, the exaggerated reflex being of minor importance. In the 
frog the same effects are produced by each, because the higher 
parts of the central nervous system being less developed than in the 
mammals, the first symptoms produced are those arising from the cord. 
Atropine differs from caffeine, on the other hand, in its effect on the 
brain, for under the latter the psychical functions are those affected 
first of all. It would seem probable, then, that each of these three 
stimulates the whole of the central nervous system more or less, but 
that while strychnine acts more strongly on the lower divisions, the 
spinal cord and medulla, and caffeine on the highest functions, the 
psychical, atropine occupies a midway position, and exercises its chief 
action on the motor divisions of the brain. These are rendered so ex- 
citable that the controlling areas can no longer keep them in check, and 
an increase in movement occurs somewhat resembling that seen when 
the controlling areas are paralyzed by alcohol. The stimulant action 
spreads downwards when large quantities have been absorbed, and 
involves the medulla oblongata and spinal cord, so that symptoms 



ATROPINE SERIES. 283 

resembling those seen in strychnine poisoning may make their ap- 
pearance. After the stimulation has lasted some time, depression sets 
in and may go on to complete paralysis of the central nervous system. 
This is fatal to mammals through cessation of the respiration, but in 
the amphibia the paralysis may pass off after some time as the poison 
is excreted, and the stage of stimulation is renewed. Even during the 
stimulation stage some symptoms of depression are to be made out, 
exactly as has been described under strychnine. 

The peripheral action of atropine involves a number cf secretory 
glands, the organs containing unstriped muscular tissue and the heart. 

Most of the Secretions are decreased by the application of atropine 

— salivary, mucous, milk and sweat. This is due not to any action 
upon the secretory cells, but to paralysis of some of the nerve ends. 
It has been investigated most carefully in the salivary glands, but 
enough work has been done on the others to show that the process 
is the same in all. The secretion of saliva in the normal animal seems 
to occur only when impulses reach the gland cells by one of two paths 

— through the chorda tympani, or through the cervical sympathetic 
fibres. If the chorda tympani be divided and put on electrodes and a 
canula be passed into Wharton's duct, a rapid flow occurs through it 
on stimulation of the nerve, which ceases or is very much diminished 
on stopping the stimulation. If now atropine be injected, stimulation 
causes no increase in the secretion and atropine, therefore, seems to 
paralyze some part of the peripheral secretory apparatus. The 
chorda tympani passes through ganglion cells on its way to the gland 
cells, and the impulses might be hindered in their passage through 
these, as actually occurs under the action of some drugs. (See Nico- 
tine.) But this is not the explanation of the inefficiency of chorda 
stimulation, as is shown by the fact that if the electrodes be pushed 
into the hilus of the gland so as to stimulate the nerve fibres beyond 
the ganglia no secretion follows. Another explanation would be that 
the gland cells themselves are paralyzed by atropine, but this is shown 
not to be the case, for on stimulating the sympathetic which supplies 
the same cells as the chorda tympani, the usual secretion follows. The 
site of action of atropine, therefore, seems to lie between the ganglion 
cells on the course of the chorda tympani and the secretory cells, that is, 
the point of attack is the terminations of the nerve fibres in the gland 
cells. The action is limited to certain definite terminations, for it has 
been noted already that the sympathetic secretory fibres are not par- 
alyzed, and it was discovered by Heidenhain that not all the fibres of 
the chorda tympani are acted on by atropine. On stimulation of this 
nerve in the unpoisoned animal, besides the increased secretion, a red- 
ness and swelling of the gland is noticed, its temperature rises, and the 
blood escapes from the veins in much larger quantity than usual and 
in spurts as if from an artery. This is due to the dilation of the 
arterioles of the gland from the stimulation of vaso-dilator fibres 
which run along with the secretory fibres in the chorda tympani. 
These fibres are not paralyzed by an injection of atropine, for on stim- 



284 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

illation of the chorda afterwards the same symptoms are produced as 
before, save that no secretion occurs. Atropine then seems to select 
the terminations of the secretory fibres of the chorda tympani for 
paralysis and to leave all others unaffected. The secretion of saliva 
seems to occur generally only on the arrival of impulses by way of the 
chorda tympani, so that on the paralysis of its terminations the secre- 
tion ceases entirely. 

In the same way the other glands of the mouth, tliroat, nose and res- 
piratory passages cease secreting after atropine, and the effect is the char- 
acteristic dryness of the mouth, the hoarseness of the voice, and the 
thirst and difficulty in swallowing complained of after its administration. 

The secretion of the gastric juice has recently been shown to be 
diminished or entirely arrested by atropine, which paralyzes the termi- 
nations of the secretory fibres of the pneumogastric nerve in the stomach. 
The hydrochloric acid of the secretion is more reduced than either the 
pepsin or the fluid as a whole. The pancreatic secretion differs from 
that of the salivary glands in the fact that it is not entirely depend- 
ent on nervous impulses, but continues after all connection with the 
central nervous system has been destroyed ; stimulation of the pneu- 
mogastric nerve has no effect after atropine, while normally it 
augments the amount of the secretion. The bile is also said to be 
somewhat lessened by atropine. The production of sugar from the gly- 
cogen of the liver has been recently shown to be controlled by branches 
of the coeliac plexus, but these have no effect after atropine, so that the 
terminations of the nerves in the liver cells seem to be paralyzed also. 

The same paralysis is produced in the terminations of the nerves in 
the sweat glands. Stimulation of the sciatic nerve as a general rule 
produces perspiration in the foot of the cat and dog, but after atropine 
this effect is absent, because the impulses cannot reach the cells through 
the paralyzed terminations, and the skin therefore becomes dry and 
hot. The secretion of milk bears the same relation to that of per- 
spiration as that of the pancreatic juice does to the saliva ; it is 
increased by stimuli from the central nervous system, but at the 
same time the mammary gland continues to secrete after all its nerves 
have been divided. Atropine therefore lessens the secretion by para- 
lyzing its nerves, but does not stop it altogether. The solids of the 
milk seem rather increased than diminished by the drug. 

The kidney is believed not to be controlled by nervous influences to 
the same extent as the glands hitherto discussed and atropine causes 
little or no change in its amount except what is probably the indirect 
result of the arrest of the other secretions. The secretion of lymph is 
not altered by atropine, so that it is probably not controlled by nerves 
in the same way as the true secretions. 

Horbaczewski states that atropine lessens the number of leucocytes 
in the blood and the uric acid of the urine. 

All Organs Containing Unstriped Muscle (apart from the arterial 
wall) seem to be altered by atropine. Thus the movements of the 
stomach, intestine, bladder, uterus, spleen, thoracic duct, and of the 



ATROPINE SERIES. 285 

pupil and oesophagus (except in animals in which these consist of striped 
muscle) are lessened by atropine. 

The movements of the stomach and intestine are generally believed 
to be arrested by small quantities of atropine, though vomiting is not 
infrequently observed in atropine poisoning, and less often a free evac- 
uation of the contents of the bowel. The exact way in which atropine 
acts here is entirely unknown, but on the analogy of its action on the 
secretory glands and on the heart it is generally supposed to be through 
its paralyzing some of the nervous apparatus with which the alimentary 
canal is so richly supplied. Previous investigators state that both the 
splanchnic and the pneumogastric nerves have no further control over 
the gastric and intestinal movements, while the former inhibits and 
the latter excites these in the unpoisoned animal; but Bayliss and 
Starling found in their recent careful experiments that atropine had 
no influence on these nerves, and in fact failed to detect any definite 
change in the movements of the intestine after enormous quantities 
of the alkaloid had been injected intravenously. Unless these authors 
were mistaken in their observations, which there is no reason to be- 
lieve, their statements involve the abandonment of the older explana- 
tion of the preliminary purgation and vomiting, which were attributed 
to atropine depressing the inhibitory endings before the exci to- 
motor. The diminution of the peristalsis, which almost invariably 
follows the administration of atropine in the normal animal, is gener- 
ally said to be due to paralysis of the ganglia of the wall, but on the 
analogy of the other organs atropine would seem to paralyze termi- 
nations rather than ganglia. 1 

Accepting this hypothesis, it is manifest that the movements are not 
finally arrested, for the intestinal muscle like the other involuntary 
muscles of the body, can maintain a regular movement without ner- 
vous impulses from without. Accordingly, any substance which irri- 
tates the muscle or perhaps even the mucous coat of the bowel, pro- 
duces peristalsis after atropine. Thus the ordinary purgatives are 
often prescribed along with atropine and act quite as efficiently as 
far as the evacuation of the bowel is concerned. Purgatives often 
produce griping pains if given alone, however, and these are relieved 
by the addition of atropine to the prescription. This has been ex- 
plained by the supposition that the griping is caused by local contrac- 
tions of the intestinal wall, which are due to nervous influence and 
therefore disappear on the application of atropine. 

Very large quantities of atropine are said to paralyze the muscle of 
the intestinal wall, but this scarcely occurs unless under special condi- 
tions, as paralysis of the respiratory centre would certainly precede it 
in the intact animal, 

x This is not altogether in opposition to the statements of Bayliss and Starling, for 
the bowel is so richly supplied with nervous plexus, that it is possible that while the 
terminations of the vagus and splanchnic are not affected by atropine, some other 
nervous structure may be put out of activity. In fact some such theory is necessary to 
explain the immediate arrest by atropine of the violent peristalsis after muscarine, which 
was noted by these authors and by all previous observers. 



286 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

Atropine exercises the same sedative effect on the movements of other 
organs as on those of the bowel. Thus, the spleSi, uterus, bladder, and 
the bronchial muscles seem less liable to contraction after its use. In 
regard to its action on the two first but little isr known, but Dreser lias 
shown that the stimulation of the pnemmoga'stric does not cause eon- 
traction of the bronchial muscle after atropine, 'while in the un poisoned 
animal it has this effect. In regard to the bladder it has been observe! 
frequently in cases of poisoning that/the urine is ejected soon after the 
ingestion of the poison, and subsequently there is a desire to micturate 
without the ability to do so. The preliminary contraction of the blad- 
der would seem analogous to that or the intestine, and the subsequent 
inability to empty it to the diminution of the peristalsis. The rhyth- 
mical contractions of the ureters are said to be accelerated by small 
doses, but to be slowed and arrested by larger amounts. 

The terminations of the nerves in the unstriped muscle of the 
oesophagus seem to be affected in the same way as in that of the intes- 
tine. A curious contrast has been noted by Luchsinger in the behavior 
of the oesophagus in rabbits and cats, in the former of which the mus- 
cle is striated, while in the latter the upper part is striated, the lower 
is unstriated. Atropine, he found, paralyzes the vagus terminations in 
those parts which are unstriped, while leaving unaffected those in the 
striped fibres. Exactly the opposite occurs after curara, which para- 
lyzes the nerve supply of the striped muscle, while leaving the unstriped 
active. Here, again, is evidence of the selective power of these poisons 
and of the difference in the chemical composition of nearly related 
structures. 

It is possible that the difficulty in swallowing, which is so well 
marked in cases of poisoning by atropine, may be due in part to the 
paralysis of the motor nerve ends, but it is generally attributed to the 
absence of the mucous secretion and consequent dryness of the pas- 
sages. 

The dilatation of the pupil by atropine has been the subject of a 
very large number of researches both by physiologists and by practical 
ophthalmologists. It occurs on internal administration as well as on 
the application of minute quantities locally, and is due to paralysis of 
the terminations of the motor nerve in the circular muscle of the iris. 
This is shown by the fact that stimulation of the motor oculi nerve or 
of the sympathetic neuron running from the ciliary ganglion is without 
effect, as well as that the dilatation may be produced by atropine in 
the excised eye. This limits the paralysis to the periphery, and that 
the muscle is not acted on is shown by its reacting to electrical stimu- 
lation. The local nature of the action may be further shown by care- 
fully applying a minute quantity of the drug to one side of the cornea, 
when dilatation of one half or less of the pupil occurs, the rest remain- 
ing contracted. The motor oculi (Fig. 26) constantly transmits irn-< 
pulses through the ciliary nerves to the sphincter muscle of the iris and 
keeps the pupil moderately contracted, and when these impulses can 
no longer reach the iris owing to the paralysis of the nerve ends, the 



ATROPINE SERIES. 



287 



sphincter relaxes and the pupil dilates. The muscle itself does not 
seem to be affected by the ordinary application of atropine, but if 
strong solutions be continuously applied, its fibres may be paralyzed 
by it as by many other drugs. The action in paralyzing the nerve 
end is universally accepted now, although it was formerly disputed. 




Diagram of the innervation of the iris. P, a fibre of the motor oculi passing from the brain to the 
ciliary ganglion {N) in which it terminates around a nerve cell, which sends an axis cylinder to ter- 
minate M, in the circular fibres of the iris. R, a spinal nerve fibre issuing from the lower cervical 
cord, running through the stellate and inferior cervical ganglia and terminating around a ganglion 
cell in the superior cervical ganglion, G. The axis cylinder from this nerve cell runs to the iris (pass- 
ing the ciliary ganglion) and terminates, C, on the radiating fibres. M indicates the terminations of 
the nerve fibre in the circular fibres, and is the point acted on by atropine and muscarine. NN', 
the ganglion cells, is the seat of action of nicotine. C, the terminations in the dilator fibres, that of 
cocaine. 



A further question is whether this is the only effect of atropine on the 
pupil, or whether the terminations of the dilating sympathetic fibres are not 
stimulated at the same time, and this cannot as yet be said to be generally 
agreed upon, although there is very strong evidence agaiust the latter view. 
Its advocates have generally ignored the fact that the constrictor muscle is 
constantly opposed by dilator fibres, and that when the former is thrown out 
of activity by the paralysis of the terminations of the motor oculi, the radiat- 
ing fibres cause an active dilatation without any stimulation of the nerve ends 
being necessary. If, however, the radiating muscular fibres be separated 
from their innervating centre by section of the cervical sympathetic nerve 
in the neck, they also cease to contract and there is no active dilatation, so 

• that atropine causes less widening of the pupil than it would if impulses 
continued to reach the radiating muscle. After the application of atropine 
to the eye, the iris often relaxes with sufficient force to tear weak adhesions 
to the lens, and this has also been held to indicate that the dilator fibres are 
stimulated, for it is unlikely that the mere passive relaxation of the iris could 



288 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

rupture an attachment. The dilatation is unquestionably an active move- 
ment, accomplished by the contraction of the radiating muscular fibres, but 
these are not put in motion by stimulation of the terminations of the fibres in 
the radiating muscles of the iris, but by the normal impulses descending from 
the central nervous system, which after atropine are not counterbalanced by 
impulses reaching the circular fibres. If the iris be attached at two points 
to the lens, atropine causes a bow-shaped dilatation between them, the eon- 
cavity being directed inwards, whereas if the dilatation were purely passive 
the part between the points of attachment would probably be loose and 
wrinkled. But this is not an argument in favor of the action of atropine, on 
the terminations of the nerves to the dilating muscle, as is often alleged, for 
it can be explained in the same way by the contraction of the dilator fibres 
due to the activity of the centre in the brain. 

In short, the evidence goes to prove that atropine dilates the pupil 
by paralyzing the terminations of the nerves in the circular muscle. 
This leaves the radiating fibres unopposed, and they, therefore, draw 
back the edge of the iris. The terminations of the nerves in the radi- 
ating muscle fibres do not seem to be affected by atropine. 

The dilatation of the pupil effected by atropine is not quite maximal, 
for stimulation of the cervical sympathetic trunk generally increases it, 
though but slightly. It differs considerably in different animals, be- 
ing more complete in man, the dog, and the cat than in the rabbit, 
entirely absent in birds and reptiles and elicited with difficulty in the 
frog. In birds and reptiles the iris consists of striped muscle fibres, 
and accordingly atropine has no action on the nerve terminations. 

In the rabbit and in man the dilatation is sometimes preceded by a 
slight contraction due, it is believed, to an irritant preparation setting 
up a reflex from the conjunctival sensory nerves. When complete dila- 
tation is attained, the pupil ceases to contract in bright light, as the 
impulses descending from the central nervous system are prevented 
from reaching the muscle, although the rest of the reflex arc is intact. 
According to several observers the pupil dilated by atropine contracts 
during narcosis from chloroform or chloral, but this statement requires 
further confirmation. 

Besides the dilatation of the pupil, a further result of the applica- 
tion of atropine to the eye is the paralysis of the accommodation. Xear 
objects are no longer seen clearly, while distant ones are as distinct as 
formerly or may be even more distinct in some eyes. The action is 
here again on the terminations of the motor nerve, in this case in the 
ciliary muscle. On local application the relaxation of the lens occurs 
later, and disappears earlier than the dilatation of the pupil, and 
larger quantities are required to produce it. 

The intraocular pressure undergoes a considerable augmentation after 
the local application of atropine as well as when it is applied through 
the general circulation. This seems to be due to the dilatation of the 
pupil, although some writers seem to believe that atropine has also a 
special action on the intraocular fluids. The increase in the intra- 
ocular pressure has been demonstrated in animals through the move- 
ments of a manometer communicating with the vitreous humor, and is 
a well-known result of the application of atropine in ophthalmology. 



ATROPINE SERIES. 



289 



It may, perhaps, explain the pain and aching in the eye and the head- 
ache complained of in some cases of poisoning, while in others these 
may be due to bright light falling on the retina, which is unprotected 
by the iris. 

Atropine paralyzes the Inhibitory Terminations of the Vagus in the 
Heart, and stimulation of this nerve therefore causes no changes in 
the pulse after its administration. A number of other drugs also 
remove the inhibitory power of the vagus, but act on a different part 
of the nerve, namely, on the ganglia. That atropine does not act here 
but on the terminations, has been shown by a number of observations. 

Fig. 27. 




Tracings of the ventricle (lower) and auricle (upper) of the dog's heart. During systole the 
levers move upwards ; during diastole, downwards. At A, the heart is noriual ; at B, the inhibitory 
fibres were stimulated, electrically, and this was continued throughout the tracing. The ventricular 
rhythm became slow and irregular, while the auricle stood still in diastole. At C, atropine sulphate 
was injected into a vein, and at D the effects of the inhibition began to pass off, although the stimula- 
tion was continued. 



Thus, in the normal frog ? s heart, and even after paralysis of the gan- 
glia on the course of the vagus, electrical stimulation of the venous 
sinus causes slowing and standstill of the heart, because the stimulus 
reaches the vagus beyond the paralyzed ganglia (Fig. 24, p. 209) ; but 
after atropine, no slowing follows stimulation of the sinus. Again, 
several drugs stimulate the ends of the vagus in the heart and act on 
parts in which no ganglia exist, but these drugs have no effect whatever 
after atropine. Small quantities of atropine have no further action on 
the heart than the paralysis of the inhibitory nerve ends. The ter- 
minations of the accelerator nerve are unaffected, exactly as the ter- 
minations of the sympathetic in the salivary glands, and the heart mus- 
cle is neither stimulated nor depressed. The heart is therefore placed 
in the same position as if the vagus were divided in the neck and, ac- 
cordinglv^ is accelerated in some animals, while in others the rhythm is 
unchanged. In the dog there is a marked quickening of the heart after 
atropine, because normally impulses are constantly transmitted from 
the inhibitory centre in the medulla, and these prevent the heart from 
beating as rapidly as it would if freed from the nervous control. In 
the cat the " tone" of the vagus is less, and the changes produced by 
atropine are correspondingly smaller, while in the rabbit and i'voiz there 
is generally no inhibitory retardation of the heart, and atropine therefore 
produces little change. In man the effects vary considerably with the 
19 



290 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

age of the patient. The inhibitory fibres seem almost inactive at birth, 
but their tone increases with age up to 25-35 years, and from this 
time lessens again and is very slight in old age. Atropine does not 
quicken the heart in the newborn child, but up to about 30 the accel- 
eration increases with the age, and from this point onwards it lessens 
again until the heart is accelerated by only 4-5 beats per minute in 
patients between 80-90 years. Along with the acceleration of the 
pulse the other effects of vagus section are also produced — increase in 
the extent of systole, decrease in the diastole and augmentation of the 
output of the heart per minute. 

Stimulation of the vagus causes no retardation of the pulse after atropine, 
but on the contrary, is not infrequently followed by acceleration from the 
presence of accelerator fibres which are not affected by atropine. 

Large quantities of atropine, besides paralyzing the vagus, weaken and 
depress the heart muscle and the contractions consequently become slower 
and weaker and the output of the heart is less than normal. Hedbom 
states that large quantities accelerate the coronary circulation in mammals 
and increase the amplitude of the contractions. He is inclined to regard the 
latter alteration as due in part to the dilatation of the coronary vessels, in 
part to a direct action on the heart muscle. 

The peripheral action of atropine hitherto discussed is due to its para- 
lyzing the terminations of a number of nerves in small doses and to its 
paralyzing the muscle or gland cells when administered in very large quan- 
tities. These facts are generally accepted as true, but a number of further 
effects have been disputed and may now be shortly discussed. 

It is not seldom stated that atropine, in addition to paralyzing the vagus 
ends, stimulates the heart muscle and thereby quickens its rhythm. This 
assertion is somewhat difficult to disprove, but none of the alleged facts 
brought forward to support it have stood closer investigation. The error 
generally arose from the belief that atropine acted on the ganglia and 
not on the nerve ends or from the use of impure and irritant preparations, 
and all the phenomena on which it was based may be explained by the 
more modern theory that the ganglia on the course of the inhibitory nerve 
fibres are left intact by atropine, while the terminations of the nerve are 
paralyzed. 

A further question is whether the nerve ends are paralyzed at once or 
whether they undergo a short stimulation first. In favor of the latter 
theory several facts may be mentioned, as that the heart in mammals is in 
rare cases first slowed and then quickened by atropine. This might indicate 
stimulation of the nerve ends, but seems due rather to the inhibitory centre 
in the medulla being stimulated before the terminations are paralyzed. This 
stimulation of the centre slows the heart until the impulses sent out from it 
are prevented from reaching the organ by paralysis of the nerve ends. The 
increase in the intestinal movements, which occurs immediately after the 
injection of atropine, might also be cited as proof of the preliminary stimu- 
lation of the nerve ends, but may also be explained by the inhibitory 
terminations being paralyzed earlier than the motor, so that these have a 
brief period of unrestrained activity. In the eye a short stage of contraction 
of the pupil not infrequently precedes the dilatation, but it is generally 
believed to be due to a reflex from the application of an irritant solution to 
the conjunctiva. Lastly, when atropine is applied to the eye of the cat a 
considerable secretion of saliva almost always follows for a short time, and 
this might be held to indicate a stimulation of the terminations of the chorda. 
It is more likely, however, that it is a reflex secretion from the bitter taste 
of the alkaloid which has escaped through the lachrymal duct into the back 
of the throat. 



ATROPINE SERIES. 291 

Several alkaloids stimulate the same peripheral nerve terminations 
as atropine paralyzes, and the interaction of the two groups is of con- 
siderable importance. It is more profitably discussed after the general 
action of these poisons has been learned, and will be taken up at that 
point (see muscarine, pilocarpine, and physostigmine ; compare also 
nicotine and the curara and coniine series). 

The voluntary Muscles are not directly aifected by atropine. The 
terminations of the motor Nerves are paralyzed in the frog by large 
doses, but this has not been elicited in mammals by ordinary meth- 
ods of experimental investigation. The terminations of the sensory 
nerves are paralyzed, or at any rate depressed by its local application. 
Thus when a liniment or ointment containing atropine is applied to 
the skin, a numbness of the part is produced and the sensation of pain 
is lessened. The local anaesthetic effect is not elicited by its internal 
administration, although it is said that the frog may be rendered less 
sensitive to irritation of the skin if poisoned with atropine. Accord- 
ing to some recent investigations the sensory terminations are first 
stimulated and then paralyzed, but the assertion stands in need of con- 
firmation. 

Circulation. — The effect of atropine on the circulation is somewhat 
complex, as, besides the action on the heart, that on the central nervous 
system must be considered. The heart is sometimes slowed and weak- 
ened at first, owing to the stimulation of the inhibitory centre in the 
medulla probably, but is generally quickened from paralysis of the in- 
hibitory fibres in the heart, and after very large doses is weakened by 
the direct action on the muscle fibre. The blood-pressure is consider- 
ably increased by the augmented output of the accelerated heart, and 
also owing to stimulation of the vaso-constrictor centre in the medulla 
which contracts the arterioles in the abdomen. The constriction of 
these vessels is accompanied by a dilation of the arterioles of the skin, 
and perhaps of the brain, from excitation of the vaso-dilator centre, 
so that the blood tends to flow from the abdominal cavity to the more 
superficial parts. The dilation of the skin vessels is, however, insuf- 
ficient to counteract altogether the contraction of those of the abdomen, 
so that a considerable increase in the arterial tension follows the in- 
gestion of atropine. The increased pressure is maintained for some 
time after small doses, while large ones lower it from the action on 
the heart muscle. The dilation of the skin vessels is more especially 
seen in the head and neck, and here produces marked flushing and 
a rash somewhat resembling that of scarlet fever. That it is due to 
central action is shown by the fact that it is prevented by division of 
the sympathetic trunk in the neck. The rash usually disappears after 
a few hours, but is sometimes followed in a day or two by desquama- 
tion. The circulation always persists after the respiration has ceased, 
and its failure is not the cause of death therefore. 

The action of atropine on the Respiration has been the subject of 
much discussion in recent years. It is sometimes slower at first through 
some unexplained central action but then becomes quicker, and ac- 



292 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

cording to most observers also deeper, and the amount of air inspired 
per minute is considerably increased. This is due to stimulation ofj 
the respiratory centre, which undergoes the same changes as the rest 
of the central nervous system. After large doses this quickened 
breathing is frequently interrupted by convulsive movements, and 
such an interruption often proves to be final. If it returns, the move- 
ments become shallower and slower in the stage of depression of the, 
nervous centres, and the failure of the respiration is the cause of death 
in fatal eases of poisoning. 

Atropine often induces a marked rise in Temperature, the cause of 
which cannot be said to be definitely known. According to Ott the 
dissipation of heat is increased, but the heat formation undergoes a 
still greater augmentation. This seems to be independent of the cir- 
culatory changes and also of the convulsions, and is attributed by him 
to direct action on the heat centres of the brain. 

Atropine is Excreted in the urine in small quantities when injected 
into the dog, but most of it undergoes complete oxidation in the tissues ; 
in the rabbit this seems to be the fate of the whole of the drug, for 
none is found in the excretions. 1 Young animals withstand much larger 
quantities than adults, according to v. Anrep because the brain is less 
highly developed and the cerebral symptoms are therefore produced 
less easily. Rabbits may be fed for weeks on belladonna leaves exclu- 
sively without showing any symptoms of poisoning, while carnivorous 
animals and man are very much more sensitive to its action. A curious 
case of poisoning is related in which the defence was made that the alka- 
loid was taken accidentally through partaking of roast rabbit, the ani- 
mal's flesh having been saturated with atropine through feeding on bella- 
donna leaves. It was found that rabbits thus fed might, in fact, con- 
tain large quantities of atropine and yet show no signs of poisoning. 
Von Anrep succeeded in developing a certain degree of Tolerance in 
dogs through repeated administration of atropine, but it was very in- 
complete. The symptoms arising from the central nervous system 
were much less evident after a few doses, while those from the heart, 
pupil and secretory glands persisted after the treatment had been con- 
tinued for some time. 

Hyoscyamine resembles atropine in its effects on the animal organism, 
but appears to have less stimulant action on the central nervous system. 
Instead of the garrulous delirium generally seen after atropine, patients 
frequently present all the symptoms of cerebral depression, fatigue, 
drowsiness and eventually sleep. This sleep is said to resemble the 
normal much more closely than that produced by opium and the hyp- 
notics of the methane series and the patient is generally more easily 
aroused and is less confused. It is by no means a constant effect of 
hyoscyamine, however, for in many cases the confusion and delirium 
described under atropine are produced instead. After atropine, sleep 
occasionally follows without any excitement, though this is much rarer 
than after hyoscyamine, but in all cases the symptoms present a curious 

1 Traces have been found in the milk of some animals and also in the foetal blood. 



ATROPINE SERIES. 293 

mixture of stimulation and depression. The difference is thus merely 
one of degree, atropine being followed by greater stimulation than 
depression, while in hyoscyamine the latter is the predominating 
feature. 

As regards the peripheral action, both produce the same effects, 
though not with equal power ; for pure hyoscyamine acts practically 
twice as strongly as atropine on the nerve terminations in the secretory 
glands, unstriated muscle and heart. But pure hyoscyamine is so 
seldom obtainable, that this is devoid of practical importance. 

Scopolamine, Hyoscine, resembles atropine closely in its peripheral 
action. The inhibitory terminations in the heart are paralyzed in 
the frog and in most mammals, and possibly in man, although most 
observers state that the pulse is not much quickened in patients and 
some state that it is slow. In regard to its action on the pupil and 
accommodation some discrepancies exist in the accounts of different 
authors. It is generally said to produce mydriasis and loss of accom- 
modation more quickly than atropine, but for a much shorter time ; 
according to Rotislaw scopolamine acts five times as strongly on the 
pupil as atropine. The effects on the central nervous system present 
the greatest divergences from those described under atropine, for the 
characteristic stimulation is absent in the great majority of cases. As a 
general rule, scopolamine produces a marked sensation of fatigue and 
drowsiness, and the patient moves about less and speaks less. Soon 
an overpowering desire to sleep is felt, and a condition in no way 
dissimilar to the natural sleep follows. In many cases, however, a 
short stage of excitement with giddiness, uncertain movements, and 
difficult and indistinct speech precedes sleep, and occasionally symp- 
toms exactly resembling those produced by atropine follow the 
administration of hyoscine. Sleep generally lasts from 5-8 hours, 
and the patient may then remain in a somnolent condition for several 
hours longer. As a general rule, after small doses no confusion is 
complained of on awakening, but dryness of the throat and thirst are 
often present. 

In one or two cases collapse has been observed after scopolamine. 
The vaso-motor and respiratory centres do not seem to be stimulated 
as by atropine, the blood-pressure falling and the respiration generally 
becoming slower from the beginning. 

In the lower animals scopolamine reduces the excitability of the 
motor areas as tested by electric shocks, while the reflex excitability in 
the frog is certainly not increased as by atropine, and according to 
some authorities is much depressed. 

The action of scopolamine then seems to correspond with that of 
atropine, save that the central nervous system is here depressed even 
more than by hyoscyamine, while the action on the peripheral nerve 
ends is somewhat stronger, and in man no distinct quickening of the 
pulse is observed. Scopolamine depresses the brain in very small 
quantities, J mg. ( T -|- 7 gr.) being generally sufficient to cause sleep. It 
does not seem to be so dangerous as the others of the series, for a dose 



294 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

of 5 mgs. (y 1 ^ gr.) has been recovered from in man, and over half a 
gramme (7 J grs.) administered to a small cat did not kill the animal. 
A certain degree of tolerance is produced after repeated use, so that 
the dose has to be increased after a week or two. 

It must be remarked that the action of scopolamine as a hypnotic 
differs considerably from that of opium and of the members of the me- 
thane series. In the first place it is very much less reliable, and in the 
second the sleep produced resembles much more nearly natural sleep. 
This difference has not been explained, but it seems probable that the 
seat of action differs in all three. 

The Other Natural Alkaloids have been less carefully examined than 
the three foregoing, and in the present state of their chemistry it is 
scarcely possible to make any definite statements regarding their action. 
" Duboisine" has been used as a hypnotic instead of scopolamine, but as 
has been mentioned, frequently consists mainly of the latter, while at 
other times the great mass of it is formed of hyoscyamine. The pseudo- 
hyoscyamine of Merck seems to be very feebly active, causing dilata- 
tion of the pupil on local application, but having little or no effect 
when given internally. 

Among the Artificial Tropeines, only one has received much attention 
at the hands of either experimental or practical therapeutists. This 
is Homatropine, a compound of tropine and oxytoluic acid, which 
is found to be less poisonous than atropine but to resemble it in the 
symptoms produced by an overdose. The mydriatic effects pass off 
much sooner than those produced by the usual solutions of atropine, 
and are said to appear more rapidly and to be less complete. It was 
formerly supposed that homatropine caused no increase in the intra- 
ocular tension, but this has been shown to be erroneous, although it is 
less active in this direction than atropine. 

Several other tropeines have been examined by Falck and Gottlieb, who 
found that they varied a great deal in their action on the lower animals. 
Many of them produce no paralysis of the oculomotor or the vagus termi- 
nations, while others act here in the same way as atropine, but differ from 
it in power. It may be stated that in general the compounds of tropine with 
the acids of the methane series possess much less of the peripheral atropine 
action than the others. It was formerly believed that even the compounds 
with the aromatic acids w r ere devoid of this action unless the acid possessed 
a hydroxyl group, but this general statement has been shown to be erro- 
neous by Gottlieb's work. A considerable variation also exists in the effects 
of the tropeines on the central nervous system, some causing excitement like 
atropine, while others act as depressants and therefore resemble hyoscya- 
mine and hyoscine. 

As has been mentioned, many of the tropeines cause no paralysis of the 
vagus inhibitory terminations but they often act as stimulants to the frog's 
heart. Tropine itself is a weakly toxic, basic substance, which in large 
quantities possesses this cardiac action, but does not paralyze the vagus nor 
the oculomotor terminations on local application. After the injection of 
large quantities, dilatation of the pupil has been observed, it is true, but this 
does not seem to be of the same origin as that produced by atropine. 

Some artificial scopoleines have been examined recently by Schiller, who 
found that they differed from scopolamine in being devoid of action on the 



ATROPINE SERIES. 295 

nerve ends in the pupil and heart and on the salivary secretion. They 
possess a certain stimulant effect on the heart muscle like some of the artificial 
tropeines, and all produce more or less depression of the central nervous 
system and narcosis. 

The action of the Crude Drugs is very similar to that of the active 
principles already discussed. The peripheral action of all of them is 
therefore almost identical in kind, though varying in degree. In 
considering their effects on the central nervous system it must be re- 
membered that those containing much atropine are more stimulant, 
those with hyoscyamine, and especially those with hyoscine, more 
sedative. In belladonna preparations the quantity of hyoscyamine 
varies a good deal, and it is said that no atropine is present in the 
fresh plant, but that during the various processes of extraction 
some or all of the original hyoscyamine becomes changed to atro- 
pine. The relative proportion of these two poisons probably varies 
in different preparations, therefore, and with it the sedative effect. 
In hyoscyamus and scopolia the presence of scopolamine and hyo- 
scyamine produces a much more narcotic effect than is obtained 
from belladonna, while datura is generally said to be less seda- 
tive than the former, but less stimulant than the latter. Duboisia 
also seems rather sedative than stimulant, but its action and that 
of its so-called alkaloid must vary considerably if the latter con- 
sists at one time of hyoscine, at another of hyoscyamine. In re- 
gard to mandrake no very recent work has been done, but its tra- 
ditional effect in causing madness would seem to entitle it to a place 
nearer belladonna than hyoscyamus. 

Preparations. 

U. S. P. — Belladonnae Folia, the leaves of Atropa Belladonna. 

Extractum Belladonna Foliorum Alcoholicum, 0.005-0.03 G. ( T V- 
\ gr.). 

Tinctura Belladonna Foliorum, 0.3-1 c.c. (5-15 mins.). 

Unguentum Belladonnse. 

Emplastrum Belladonna. 

Belladonnae Radix, the root of Atropa Belladonna. 

Extractum Belladonnas Radicis Fluidum, 0.05-0.1 c.c. (1-2 mins.). 

Linimenttjm Belladonna, containing camphor. 

Hyoscyamus, the leaves of Hyoscyamus niger, henbane. 

Extractum Hyoscyamt, 0.03-0.2 G. (J-3 grs.). 

Extractum Myoscyami Fluidum, 0.3-1 c.c. (5-15 mins.). 

Tinctura Hyoscyami, 1-4 c.c. (15-60 mins.). 

Stramonii Semen, the seeds of Datura Stramonium. 

Extractum Stramonii Seminis, 0.03-0.1 G. (£-2 grs.). 

Extractum Stramonii Seminis Fluidum, 0.06-0.2 c.c. (1-3 mins.). 

Tinctura Stramonii Seminis, 0.5-1.5 c.c. (8-20 mins.). 

Stramonii Folia, the leaves of Datura Stramonium. 

B. P. —Belladonnae Folia, the fresh leaves and branches of Atropa Bella- 
donna. 

Extractum Belladonnse Viride, |-1 gr. 

Succus Belladonnse, 5-15 m. 

Belladonnae Radix, the root of Atropa Belladonna. 



296 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

Extractum Belladonna Alcoholicum (1 per cent, of alkaloids), \-\ gr. 
Extractum Belladonna Liquidum (f per cent, of alkaloids), \-\ min. 
Tinctura Belladonna (2V per cent, alkaloids), 5-15 mins. 
Linimentum Belladonna. 
Unguentum Belladonnas. 
Emplastrum Belladonna. 

Suppositoria Belladonnse, each containing -$■$ gr. of alkaloids. 
Hyoscyami Folia, the fresh leaves, flowers and branches of Hyoscyamus 
niger, henbane. 
Extractum Hyoscyami Viride, 2-8 grs. 
Tinctura Hyoscyami, |-1 fl. dr. 
Succus Hyoscyami, |-1 fl. dr. 

Stramonii Folia, the dried leaves of Datura Stramonium. 
Tinctura Stramonii, 5-15 mins. 

Stramonii Semina, the seeds of Datura Stramonium. 
Extractum Stramonii, \—l gr. 

Alkaloids. 

Atropina (U. S. P., B. P.), an alkaloid (C 17 H 2? N0 3 ) derived from bella- 
donna and forming white, acicular crystals, very little soluble in water, but 
soluble in alcohol and ether, and having a bitter taste. 0.0005-0.001 G., 
£-1 mg. (aijo-iio g r - B - P )« 

Atropina Sulphas (U. S. P., B. P.), a white, crystalline powder, w T ith a 
very bitter taste, soluble in water and alcohol. Dose, as for atropine. 

Unguentum Atropinse (B. P.), 4 per cent. 

Liquor Atropinse (B. P.), 1 per cent., \-l min. 

Lamellse Atropinse (B. P.), gelatin discs each containing T ^ gr. of atro- 
pine sulphate. 

Hyoscyamina Sulphas (U. S. P., B. P.) ((C 17 H 23 N0 3 ) 2 H 2 S0 4 ), the sul- 
phate of an alkaloid derived from Hyoscyamus niger. A crystalline, deli- 
quescent powder with a bitter acrid taste, very soluble in water and alcohol. 
O.'0005-O.OOl G., i-1 mg. ( T ^- 5 V gr.). 

Hyoscyamina Hydrobromas (U. S. P.), the hydrobromate of hyoscya- 
mine, resembles the sulphate in most points, but is not deliquescent. Dose, 
as of the sulphate. 

Hyoscina Hydrobromas (U. S. P.), Hyoscina Hydrobromidum (B. P.), 
(C 17 H 21 N0 4 HBr, 3H 9 0), the hydrobromate of hyoscine or scopolamine. It 
is obtained from hyoscyamus, scopolia and other solanacese, and forms color- 
less, transparent crystals with an acrid bitter taste and is very soluble in 
water, less so in alcohol. 0.0003-0.0005 G., %-h mg. (oiro~T<To gr.)- 

Homatropina Hydrobromidum (B. P.) (C 16 H 21 N0 3 HBr), the hydro- 
bromide of an alkaloid prepared from tropine, a white crystalline powder, 
soluble in 6 parts of cold water. 

Lamellse Homatropinse (B. P.), homatropine discs, each weighing 5V gr. 
and containing T ^o gr. of homatropine hydrobromide. 

Non-official preparations are the sulphate and hydrobromate of Duboisine, 
which have been recently introduced. They are given in the same quantities 
as atropine salts. 

Therapeutic Uses. — The numerous changes produced by atropine and 
its congeners on the organism would indicate for them a very wide 
sphere of usefulness were it possible to elicit their action on one organ 
without affecting others and this difficulty may perhaps be overcome 
in the future, when the different individuals of the series have been 
more carefully compared, and new tropeines and other modifications 
of the tropine radicle are available in therapeutics. 






ATROPINE SERIES. 297 

The peripheral action of the whole series, as far as it is at present 
known, is so uniform that any member might be used to elicit it, 
but the only one that has come into general use for its peripheral 
effects is atropine. The purposes for which atropine is employed may 
be divided into groups as follows : 

To Arrest or Lessen Secretions. — In rare cases of excessive salivation 
atropine has proved of service, but it is much more frequently used to 
lessen the perspiration, especially in the later stages of phthisis. For 
this purpose comparatively small quantities, such as \ mg. (j-g-Q- gr.) 
given by the mouth or hypodermically are generally sufficient, or the 
extract or tincture of belladonna may be used instead. In local 
sweating, it is often applied locally in the form of an ointment, lini- 
ment, or plaster, although Tappeiner has found that it has no effect 
when thus employed. Atropine is also used to arrest the secretion of 
the milk, for although it has not the immediate effects on the mammary 
that it possesses on the salivary glands, the secretion is diminished and 
eventually ceases under its influence, which prevents the gland receiv- 
ing any stimulation from the central nervous system. Belladonna is 
usually applied locally for this purpose in the form of the plaster, or 
less commonly of the ointment or liniment. 

To Paralyze the Cardiac Inhibitory Terminations. — For this purpose 
a slightly larger quantity is required than is necessary to stop the secre- 
tions, and the administration of sufficient atropine to paralyze the vagus 
(1 mg.) therefore involves unpleasant dryness of the throat and diffi- 
culty in swallowing. In cases where slowing of the heart tends to be 
dangerous in itself, more especially in poisoning with certain substances 
to be discussed later, atropine is indicated. It may also be used for 
diagnostic purposes, to find if bradycardia is due to disease of the heart 
muscle or to inhibition. It may be repeated here that the resultant 
quickening is much less in old than in middle-aged people, and it is 
said that in many cases of old valvular lesion the administration of 
atropine is followed by little or no acceleration. Some forms of inter- 
mission of the pulse are due to unusual activity of the inhibitory appa- 
ratus, and these may be remedied by atropine ; but this intermission 
possesses little importance, and seems to require no therapeutic treat- 
ment. Atropine may be used to diagnose it from the more significant 
forms present in organic disease of the heart. The use of atropine to 
paralyze the vagus terminations before the administration of an anaes- 
thetic has been discussed already. (See page 176.) 

To Paralyze the Terminations of the Motor Nerves in the Iris and 
Ciliary Muscles. — It is used for this purpose largely in ophthalmology 
as a means of diagnosis and of treatment, and the precise conditions in 
which it is indicated may be treated better in text-books on this sub- 
ject than here. For these objects, solutions of the alkaloid al salts are 
generally applied to the conjunctiva, when enough of the alkaloid passes 
into the eye by a process of imbibition to produce marked local effects 
without affecting more distant organs. In order to dilate the pupil, 
extremely dilute solutions are used ; a few drops of a solution of one in 



298 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

1,000, or even of one in 10,000, are quite sufficient. Much stronger 
solutions are required to paralyze the accommodation, and as a general 
rule 1 per cent, is used. These strong solutions produce complete 
paralysis in 1—1 J hours, and the accommodation does not recover 
completely until after 5-7 days, while the pupil may not regain its 
normal size for 10-14 days. The application of even weaker atropine 
solution renders the sight imperfect for an inconveniently long period, 
and hyoscine and homatropine are therefore much used in its stead. 
The symptoms produced by a 1 per cent, solution of homatropine pass 
off, or at any rate become very much less marked in the course of 36 
hours. These are consequently preferable for diagnostic purposes, 
while atropine is rather to be used where it is desirable to produce a 
paralysis of longer duration, as in various inflammatory conditions of 
the iris or cornea. Atropine is also preferable where complete paralysis 
of the accommodation is necessary, as homatropine often fails to effect 
this. Atropine and its congeners are contraindicated where there is 
any suspicion of glaucoma, as, owing to their action on the intraocular 
pressure, they may either aggravate the disease already present or pre- 
cipitate an acute attack. When dilatation of the pupil is necessary and 
there is reason to apprehend the results on the intraocular pressure, 
homatropine should be employed as its effects can be readily controlled 
by eserine. Numerous cases of poisoning have arisen from the exten- 
sive use of atropine in diseased conditions of the eye. It is often 
asserted that it passes down with the tears through the lachrymal duct 
and is absorbed from the nose, throat and stomach, but as a matter of 
fact it may be absorbed from the conjunctiva itself. The symptoms 
are generally only the milder ones of atropine poisoning — dryness of 
the throat and slight excitement — but dangerous and even fatal poison- 
ing has also arisen from its local application. In many cases this is 
due to the application of unnecessarily strong solutions to the eye, but, 
on the other hand, some patients seem abnormally sensitive to the 
action of atropine, and hyoscine, or better homatropine, ought to be 
preferred. In rare cases a curious inflammatory condition of the con- 
junctiva is set up by atropine, and this is often supposed to be due to 
the use of irritant preparations, but sometimes seems to follow the 
application of the absolutely pure alkaloid, and is apparently an idio- 
syncrasy ; it may, perhaps, be explained by the arrest of the ordinary 
secretions of the lachrymal gland and conjunctiva in these cases. 
Sometimes discs of gelatin impregnated with atropine or homatropine 
sulphate (B. P.) are applied to the conjunctiva instead of solutions of 
the salts. 

To Relax Spasm of the Intestines. — In various forms of colic atro- 
pine is of very great service in lessening pain and allowing the passage 
of the intestinal contents ; for instance, it is preferable to morphine in 
lead colic, as it does not cause constipation. Hernia and volvulus are 
sometimes reduced by atropine injected hypodermically (3 mg. or ^ 
gr.). It is often prescribed along with purgatives in order to lessen 
the griping which they produce, and has been used as a laxative in 



ATROPINE SERIES. 299 

some forms of constipation with considerable success. For action on 
the bowel it is generally prescribed in pill form as one of the extracts 
of belladonna or hyoscyamus. The object of prescribing an impure 
preparation instead of the alkaloid is to allow of a strong local action 
along the intestinal wall along with a slow and imperfect absorption, 
as the pure alkaloidal salts are liable to be absorbed in the stomach. 

To Relax Spasms of the Involuntary Muscles of Other Organs. — In 
the spasmodic contraction of the ureters and bile ducts due to calculi, 
atropine is occasionally prescribed either in the form of a pill or in 
solution for internal use, or by hypodermic application. In some forms 
of asthma supposed to be due to contraction of the bronchial muscles, 
atropine has been applied locally by means of a spray or given inter- 
nally, and stramonium leaves are often found of benefit when made up 
into cigarettes and inhaled when the attack comes on. Some cases of 
asthma are said to have been permanently cured by treatment with 
atropine internally. An ointment of atropine has also been applied to 
the cervix uteri with the hope of relaxing spasm during labor, but the 
results are somewhat questionable. Perhaps this action in relaxing 
spasmodic contractions of nervous origin may also explain the beneficial 
effects obtained in cases of incontinence of urine in children in which 
belladonna has long been the most reliable remedy. 

To Lessen Pain. — Belladonna liniment, plaster and ointment have 
long enjoyed a considerable reputation as local anodynes and atropine 
has not infrequently been injected into painful areas. This anodyne 
action is very weak compared with that of cocaine, however, and the 
preparations of atropine have been less used of late years. In some 
forms of gastralgia atropine has also been suggested. 

The Effects on the Central Nervous System of the members of this 
group are very different, and the purposes for which they are used are 
diametrically opposite. Atropine is used as a stimulant in various 
conditions of depression of the brain and medulla oblongata. Thus, 
in collapse its hypodermic injection may be of use to stimulate the 
respiratory and vaso-constrictor centres, and at the same time to free 
the heart from excessive inhibition. In dangerous poisoning from 
narcotic and hypnotic drugs, more especially in opium poisoning, 
atropine has been largely used. A long and weary dispute as to the 
value of atropine in those cases has been carried on, for the history of 
which the reader is referred to the recent paper by Bashford. The 
results indicate that atropine is useful in morphine poisoning through 
stimulating the respiratory centre, which is the danger point. But it 
must be employed in small quantities (1.5 mg. or fa gr.) as large 
doses, such as have frequently been advised, tend to depress the central 
nervous system and thus to aid rather than to antagonize the action of 
morphine on the respiration. It may be questioned whether in any 
case atropine may not be replaced by caffeine with advantage. The 
former stimulates the medullary centres but subsequently paralyzes 
them, while caffeine, even in comparatively large quantities, does not 
seem to have a depressant action in man. 



300 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

Atropine at one time had some reputation in the treatment of epi- 
lepsy. It has been shown botli clinically and experimentally that this 
reputation was undeserved, the number of attacks and their violence 
being rather increased than diminished by its exhibition. Possibly the 
belief in its powers arose from the use of impure preparations contain- 
ing hyoscy amine or hyoscine. 

In some spasmodic diseases, such as whooping-cough, belladonna 
preparations have long enjoyed a wide reputation ; a possible explana- 
tion is that the hyoscyamine may allay the spasms by reducing the 
excitability of the respiratory centre. 

Hyoscyamine and more recently hyoscine or scopolamine have been 
used as narcotics to depress the central nervous system ; they are said 
to be of great efficacy in insanity, producing sound and refreshing sleep, 
but are of less value in controlling the excitement during the day, and 
may, in fact, increase it. Hyoscine is also used with benefit in various 
forms of tremor of central origin, and is said to lessen sexual excite- 
ment. Its hypnotic action does not seem to be of the same nature as 
that of opium, for in sleeplessness produced by pain it is of compara- 
tively little value, and it has no power to relieve pain itself. It differs 
from chloral in not producing deep sleep, for patients under the influ- 
ence of hyoscine can always be aroused and are much less confused 
than after chloral. The special indications for hyoscine seem to be 
sleeplessness due to abnormal activity of the motor areas, and some 
forms of tremor. 

Poisoning. — In cases of poisoning with belladonna and its allies the 
treatment is purely symptomatic. In the excitement stage sedatives 
may be used ; perhaps chloroform and ether are best, as their effects 
are more transient than the others. Morphine has been advised, but 
its action on the respiratory centre renders its use dangerous, as in 
severe atropine poisoning the stimulation soon passes into depression, 
and the effects of the poison and its so-called antidote therefore sup- 
plement each other. Chloroform and ether, on the other hand, may 
be used to control the spasms and then stopped when these pass off". 
In the depression stage caffeine may be used, and eventually artificial 
respiration. 

Bibliography. 

Bezold u. Bloebaum. Untersuch. a. d. physiol. Laborator. zu Wiirzburg, i., p. 1. 

Keuchel. Inaug. Diss., Dorpat, 1868. 

Heidenhain. Pfluger's Archiv, v., p. 309, and ix., p. 335. 

Luchsinger. Ibid., xv., p. 482 ; xviii., p. 587, and xxvi., p. 459. 

Albertoni. Arch. f. exp. Path. u. Pharm., xv., p. 258. 

Hammerbacher. Pfluger's Arch., xxxiii., p. 228. 

Mironow. Arch, de Scienc. biologique, iii., p. 353. 

Binz. Centralbl. f. klin. Med., 1893, p. 25. 

Ott. Therap. Gaz., 1887, p. 511. 

Alms. Arch. f. Anat. u. Phys., 1888, p. 416. 

Surminsky. Ztschr. f. rat. Med., xxxvi., p. 205. 

Bayliss and Starling. Journ. of Physiol., xxiv., p. 99. 

Riegel. Ztschr. f. klin. Med., xxxvii., p. 381. 

■Schiff. Arch. f. Verdauungskrankh., vi., p. 107. 

Gottlieb. Arch. f. exp. Path. u. Pharm., xxxvii., p. 218. 



ATROPINE SERIES. 301 

Rnbo'jo. Therap. Monatsheft, 1893, p. 410. (Duboisine.) 
Heubich. Arch. f. exp. Path. u. Pharrn., viii., p. 31. 
Graser. Ibid., xvii., p. 329. 
Lenhartz. Ibid., xxii., p. 337. 

Vollmer. Ibid., xxx., p. 385. 

Levison. Berl. klin. Woch., 1894, p. 891. 

Orlowski. Diss., Dorpat, 1891. 

Mailer. Diss., Dorpat, 1891. 

Mathews. Am. Journ. of Physiol., iv., p. 482. 

Wood. Therap. Gaz., 1885, p. 1. (Hyoscine. ) 

Robert. Arch. f. exp. Path. u. Pharm., xxii., p. 396. (Hyoscine.) 

De Stella. Arch, de Pharmacodynamique, iii., p. 381. 

Friedldnder. Therap. Monats., 1894, p. 533. (Hyoscine.) 

Schiller. Arch. f. exp. Path. u. Pharm., xxxviii., p. 71. 

Anrep. Pfliiger's Archiv, xxi., p. 78. 

Schultz. Arch. f. Anat. u. Phys., 1898, p. 53. 

Thompson. Ibid., 1894, p. 117. 

Walti. Arch. f. exp. Path. u. Pharm., xxxvi., p. 411. 

Strieker u. Spina. Wiener Sitzungsbericht, Math.-nat. Classe, lxxx., Abt. iii., p. 
117. 

Spiro. Arch. f. exp. Path. u. Pharm., xxxviii., p. 113. 

Wiechowski. Ibid., xlvi., p. 154. 
Hedbom. Skandin. Arch. f. Phys., viii., p. 171. 

Compare also the Literature of pilocarpine and muscarine, nicotine and physostig- 
mine. 

Agaricin. 1 

White Agaric (Agaricus albus, Boletus Laricis), a fungus growing 
on the European larch tree, was formerly a purgative and antihydrotic 
of some repute. Its use to lessen the perspiration (antihydrotic) has 
been revived of late years, or rather a preparation known as agaricin 
and containing the active principle has been introduced into thera- 
peutics. Agaric or Agaricinic acid, the active constituent, belongs to 
the malic acid series and has the formula C u H 27 (OH)(COOH) 2 . 

Action. — Both the acid and its sodium salt irritate the mucous membranes 
and wounded surfaces, and cause inflammation and even suppuration when 
injected subcutaneously. Large quantities irritate the stomach and intestine 
and cause vomiting and purging, but these are more liable to arise from the 
impure agaricin owing to its containing resinous acids. Injected into the 
frog, agaric acid paralyzes the central nervous system, weakens the heart 
and stops the secretion of the skin glands. In mammals the intravenous 
injection of agaric acid is followed by depression, weakness, dyspnoea and 
death. The medulla oblongata is first stimulated and then paralyzed, as is 
shown by the blood-pressure first rising and then falling to zero, while the 
heart is primarily slowed by inhibitory action and later regains its rhythm, 
to eventually fail after the arrest of the breathing. Animals can only be 
poisoned with difficulty by the subcutaneous injection of agaricin, and no 
general symptoms are elicited when it is administered by the mouth. 

The most interesting feature of the action of agaric salts is the arrest 
of the sweat secretion, which is caused by peripheral action, for stimu- 
lation of the nerves of the cat's foot fails to elicit perspiration after its 
ingestion. It thus acts on the same peripheral mechanism as atropine 
in all probability, that is, on the terminations of the secretory nerves, 
but differs from atropine in acting only in the sweat glands, for the 

1 Agaricin does not resemble atropine in its general action, nor in its chemical prop- 
erties, but it may be inserted at this point until these are more fully elucidated. 



302 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

saliva, tears and other secretions are not hindered by it, and may, in 
fact, be increased by its causing nausea. It is also devoid of action 
on the nerve terminations in the heart and pupil. Atropine acts much 
more powerfully than agaric acid, at least twenty times as much of the 
latter being required to arrest the sweat secretion. 

Uses. — Agaricin is used in the night sweats of phthisis and other 
similar conditions and is generally given in pill form in doses of 5-60 
mgs. (iV - 1 g r -)- ^ ne commercial agaricin often contains a large per- 
centage of impurities and has to be given in larger quantities, but the 
treatment ought to be begun with small doses. Tolerance is said to be 
acquired after some time, and the dose has then to be increased. The 
best results are got when the pills are taken 5-6 hours before retiring, 
as the acid is only slowly absorbed. If agaricin causes intestinal 
irritation and diarrhoea it may be given with opium, but as in phthisis 
all irritation of the bowel is to be avoided, the remedy ought perhaps 
to be stopped when any such disturbance arises. 

Other antihydrotics are atropine and camphoric acid. Agaricin is 
preferable to atropine, because the latter tends to cause dryness of the 
throat and other symptoms when it is given for some time even in 
very small doses. 

Bibliography. 

Hofmeister. Arch. f. exp. Path. u. Pharm., xxv., p. 189. 



XIV. COCAINE. 

Cocaine is a comparatively recent addition to therapeutics, although 
the coca plant has been in use in South America for centuries. It is 
indigenous there, but has been introduced into India, Ceylon and Java. 
The leaves of the coca grown in Peru and Bolivia contain cocaine 
along with small quantities of other alkaloids, but the India coca and 
still more the Java leaves contain a smaller proportion of cocaine and 
a larger amount of the less known alkaloids. 

Cocaine, like atropine, is readily decomposed into several constitu- 
ents. On heating it with water, methyl alcohol is thrown off, leaving 
Benzoyl-ecgonine, which may be further broken up into benzoic acid 
and JEcgonine, a pyridine derivative. 

Ecgonine. Cocaine. 

CH„— CH CH-COOH CH — CH CHCO-OCH, 

II I 2 I I 

N(CH)CH-OH N(CH)CH-0-CO-C H 

| 3 , I ! S| 6 5 

CH 2 -CH CH 2 CH 2 — CH CR~ 2 

Cocaine is capable of being changed in several different parts of its struc- 
ture. Thus ethyl or propyl may be substituted for the methyl group, the 
benzoyl radicle may be replaced by various others, such as cinnamyl, and so 
on. Many artificial cocaines have been formed in this way, and several of 
these have since been found in the cultivated plant, as for example Cinna- 
myl-cocaine, in which cinnamyl occupies the position of benzoyl in the above 
formula Various other alkaloids, such as Cocamine, Isococamine, Homococa- 



COCAINE. 303 

pine and Homoisococamine are also present ; all of these contain the ecgonine 
molecule in combination with various acids, and cocaine may be formed from 
all of them by isolating the ecgonine and combining it with benzoic acid and 
methyl. These alkaloids are present in the plant in very small quantities 
compared with cocaine and have not been used therapeutically. 1 Another 
alkaloid which has been found in the Java coca is Tropacocaine, which is a 
combination of benzoic acid and a base (C 8 H 15 NO) which was formerly sup- 
posed to be identical with the pseudotropine derived from hyoscine, but has 
been shown to be of different constitution. It will be observed that the 
formula of ecgonine resembles very closely that of atropine, each containing 
the same nucleus, but differing slightly in the radicles attached to it. 

The most important effects of cocaine are those on the central nerv- 
ous svstem and on the sensory nerves. 

Symptoms. — The symptoms of cocaine poisoning in man vary a good 
deal in different individuals. In most cases small quantities produce 
some excitement, pleasurable or disagreeable. The patient is gener- 
allv restless and more garrulous than in ordinary life, often somewhat 
anxious and confused. But very often a small dose is followed by a 
calm, languorous state, somewhat resembling that induced by small 
quantities of morphine, but differing from it in there being less tend- 
ency to sleep. The pulse is accelerated, the respiration is quick and 
deep, the pupil generally dilated, and headache and dryness of the 
throat are often complained of. The reflexes may be found somewhat 
more easily excited than usual and tremors or slight convulsive move- 
ments often occur. Later powerful tonic or clonic convulsions super- 
vene, the heart becomes extremely accelerated, the breathing becomes 
rapid and dyspnceic and may be finally arrested during a convulsion. 
In other cases the convulsive seizures are almost entirely absent and 
fainting and collapse occur. The skin is cyanotic and cold, the heart 
slow and weak ; the respiration is very much depressed and death fol- 
lows from its gradual cessation. Vomiting is occasionally seen at an 
early stage, but is not by any means common. 

In the dog, cat and rabbit the symptoms are invariably those of 
stimulation of the central nervous system. Soon after the injection, 
the animal shows symptoms of great restlessness and excitement ; it 
seems unable to keep still, the dog at first showing all the signs of 
affection and excitement which he displays on ordinary occasions on 
being unchained or taken for a walk, but afterwards running continu- 
ally in a circle and paying but little heed to anything around him. 
Still later regular convulsions occur, and these are at first clonic but 
may afterwards become tonic, and then resemble those seen in strych- 
nine poisoning. Even before the convulsions appear the animal seems 
partially unconscious, and in the intervals between them he lies in an 
apathetic state, which soon deepens to coma and death from asphyxia. 

In the frog a certain amount of stimulation of the central nervous 
system is often displayed after small doses — increased movement, exag- 
gerated reflex and occasionally convulsions — but these soon pass into 

1 Hygrine, which \ 
not to exist in them. 



304 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

depression and eventually total paralysis of the central nervous system, 
while the peripheral nerves still maintain their functions. 

General Action. — Many of these symptoms point to a stimulant 
action on the Central Nervous System, resembling closely that seen in 
atropine poisoning. Thus the garrulity which is so often produced by 
cocaine, indicates an increased activity of the cerebrum, and the in- 
creased movement in the lower animals distinctly points to an affection 
of this part of the brain, for the movements are perfectly coordinated, 
and, in fact, in the early stages resemble exactly those performed by 
the normal animal in a condition of excitement. Further evidence of 
the action of cocaine on the cerebrum is offered by its effects on mus- 
cular work. The natives of Peru and Bolivia have used it for cen- 
turies to increase their endurance of fatigue. The bearers of the 
Andes, for example, march for hours and days with very little rest or 
food when they are supplied with coca leaves to chew. The effects of 
cocaine on the muscular power and on fatigue have been investigated 
also by means of the ergograph and dynamometer, and all observers 
are at one in asserting that much more work can be done after cocaine 
than before it, and that it has a surprising potency in removing fatigue. 
As regards mental work, its effects are less known, but on the analogy 
of caffeine it may be supposed to increase the mental powers also when 
taken in small quantities. Some travellers in South America relate 
marvellous tales of its producing feelings of the highest bliss and 
power, but these have not been confirmed by experience in the action 
of cocaine in less romantic regions of the globe. Cocaine in small 
quantities, then, increases the higher functions of the cerebrum, while 
in somewhat larger doses the stimulant effect spreads to the lower areas 
and produces a very great increase in movement, accompanied, it w r ould 
seem, by a depression of the consciousness. At the same time, the 
coordinating or balancing powers seem affected, so that the animal 
generally moves in a circle, the symptoms resembling the forced move- 
ments often seen in affections of the cerebellum. 

The motor areas of the cerebrum have been found to be more easily 
stimulated by the electric shock when cocaine is injected, though when 
it is painted on the surface of the brain it lowers the irritability, owing to 
its action as a general protoplasm poison. Still larger quantities induce 
convulsions, which are not of spinal origin, but point rather to action 
on some undetermined part of the hind brain. At an early stage the 
medulla oblongata is affected, as is shown by the quickened respiration, 
and the exaggerated reflexes indicate stimulation of the spinal cord, 
which may be so great after very large doses as to cause convulsions 
like those produced by strychnine. The action of cocaine on the cen- 
tral nervous system is primarily a descending stimulation, the cere- 
brum being first affected, then the hind brain and medulla oblongata, 
and last of all the spinal cord. Perhaps it might be better expressed 
by saying that after small quantities the chief symptoms arise from 
the cerebrum, but as the dose is increased those from the lower parts 
of the central axis tend to become more prominent. After the stimu- 



COCAINE. 305 

lation there succeeds depression, which follows the stimulation down- 
wards, affecting first the cerebrum and then the lower divisions. The 
two stages are not definitely divided, however, one part of the cere- 
brum often showing distinct depression, while another is still in a con- 
dition of excessive activity. In some cases, especially in man, the 
stage of excitement may be very short or apparently entirely absent, 
and the whole course of the symptoms then points to depression. 

The Eespiration after cocaine is much accelerated owing to central 
stimulation. At first the depth of the movement is not changed, but 
as the acceleration progresses, the air inspired with each breath gradu- 
ally becomes less. During the convulsions the respiration is irregular 
or ceases, but it recovers again in the intervals, until after a very vio- 
lent paroxysm it fails to be reinstated. In other cases the breathing 
becomes slower and weaker after a time, and eventually stops from 
paralysis of the centre. Periodic respiration is frequently seen, of the 
form generally known as Cheyne-Stokes'. (See Morphine, p. 213.) 

The Circulation is altered by cocaine owing to its action on the 
heart and on the vessels. The heart is much accelerated in mammals, 
while in the amphibians this is less often observed. The quickening 
has been ascribed to paralysis of the inhibitory terminations, but this 
seems not to be the case, for stimulation of the vagus slows the heart 
even late in the poisoning. The heart is accelerated, then, either by 
direct action of the muscle or by stimulation of the accelerator mech- 
anism. It is often slow before death, but apparently not invariably, 
and this is probably due to direct action on the muscle. In the frog's 
heart the inhibitory apparatus is paralyzed, the ganglia being affected 
in the same way as by coniine and other drugs. 

The vessels are much contracted in the earlier stages of poisoning, 
and this, together with the increased rate of the heart, leads to a very 
considerable rise in the blood-pressure. The constriction of the vessels 
seems partly due to stimulation of the vaso-constrictor centre, for sec- 
tion of the splanchnic nerves leads to an immediate depression of the 
arterial tension. But cocaine also exercises a direct action on the 
vessel walls, for its local application leads to constriction of the vessels 
and blanching of the mucous membranes. It has not been determined 
as yet how far this direct action on the vessel walls affects the blood- 
pressure when cocaine is absorbed or when it is injected intraven- 
ously. The blood-pressure subsequently falls, apparently from periph- 
eral action, if Anrep's assertion that stimulation of the splanchnic 
then produces no further rise of pressure be correct. 

The effects on the peripheral Nerves and Muscles are disputed, for 
Mosso states that small quantities increase the strength of the muscular 
contractions on electrical stimulation both in man and animals, while 
others have failed to obtain any such effect. 

After the injection of cocaine, Anrep observed marked pallor of the 
Intestine and powerful peristalsis, while very large doses caused dila- 
tation of the mesenteric vessels and lessened the movements of the 
bowel probably through paralyzing the local nervous mechanism. 
20 



306 ORGANIC DRUGS ACTING AFTER ABSORPTION 

The Urine is sometimes said to be increased by cocaine, while in 
other instances its injection has been followed by total anuria lasting 
for several hours. This suggests that the action is not a direct one on 
the kidney, but is caused merely through the changes in the calibre of 
the vessels. 

The other Secretions seem rather decreased than augmented, but no 
very marked effects are produced on them. 

The Temperature is generally increased in cases of poisoning, some- 
times rising as much as 3-5° C. above the normal, apparently from 
some disorder of the heat-regulating centres of the brain. Langlois 
and Kichct observed that the higher the temperature of the animal, 
the more easily were convulsions produced by cocaine and the more 
severe their type. 

It used to be supposed that cocaine retarded the Tissue Change and 
that less food was required when it was supplied. This was based on the 
statement of the endurance of the natives of South America when they were 
allowed to chew coca leaves, and on the discovery that the leaves also allay 
hunger to some degree. But the increase in the working power is due to 
the effects on the central nervous system, while the craving for food is prob- 
ably lessened owing to the cocaine inducing numbness of the sensory nerves 
of the stomach through its local action. 

A curious effect of cocaine, noted by Ehrlich in mice, is a widespread 
destruction of the hepatic cells, which become vacuolated and often 
necrosed. The liver is much increased in size and looks pale from fatty 
infiltration, which is also present, but which is not so characteristic as the 
vacuoles. 

Some cocaine is Excreted by the kidney in the dog when it is ab- 
sorbed into the blood, but 95 per cent, of that ingested is destroyed in 
the tissues, and this is the fate of all of it in the rabbit, in which this 
oxidation proceeds very rapidly. It is unknown whether it is oxidized 
in man, who is much more susceptible to its action than these animals. 

Local Action. — Cocaine applied locally in most parts of the body 
produces a loss of sensation through its paralyzing the Terminations of 
some of the Sensory Nerves, particularly those conveying impressions 
of pain and touch. It is often stated that the end organs of the nerves 
concerned with the feeling of heat and cold are also disorganized, but 
the exact researches of Kiesow show that this is incorrect, and that 
heat and cold are recognized as readily as in the unaffected parts of the 
body. Cocaine applied to the tongue removes the taste of bitter sub- 
stances, while sweet and acid fluids lose their taste only partially, and 
salt is recognized as easily as usual. 1 A solution applied to the nasal 
mucous membrane paralyzes the sense of smell entirely. The anaesthesia 
or insensibility to pain and touch may be induced in any of the mucous 
membranes that can be reached by cocaine in sufficient concentration, 
pharynx, larynx, oesophagus, stomach, nose, eye, urethra, bladder, 

1 A curious contrast is presented in this respect by gymnemic acid, which is obtained 
from the Gymnema silvestre, and which removes the sensation of sweetness, while 
''bitter" is less affected and "acid" and "salt" are recognized as readily as usual. 
Gymnemic acid does not affect any other sense organs, as far as is known, and is, in 
fact, devoid of interest, except as regards its effect on taste. 



COCAINE. 307 

vagina and rectum. Applied to the unbroken skin its effects are less 
marked, as it penetrates but slowly through the horny epidermis ; but 
when the epidermis is removed by abrasions or by skin disease, the 
cutaneous organs of sensation are acted on in the same way as those of 
the mucous membranes. The deeper sensory terminations can also be 
acted on by hypodermic injection, which causes a feeling of numbness 
and the relief of pain in the part. Hypodermic injection reaches not 
only the nerve terminations of the subcutaneous tissues, but also the 
finer nerve bundles, and these too are rendered insensible as far as the 
solution extends to them. The part may therefore be cut into or be 
subjected to other surgical treatment without pain, as long as the knife 
does not pass beyond the area to which the drug has penetrated, and 
numbers of grave surgical operations have been performed under the 
local anaesthesia produced by cocaine. Injected into the neighborhood 
of a nerve trunk, cocaine penetrates into the fibres and induces anaes- 
thesia of the organs supplied by the nerve, and injected into the spinal 
canal, causes anaesthesia over large areas of the body, sometimes over 
almost the whole body ; this is probably due to its acting on the pos- 
terior roots of the cord. It must be noted that the anaesthesia is only 
produced by the local application of the drug. The internal admin- 
istration only leads to a partial loss of sensation in the throat and 
stomach, and no anaesthesia is induced by its action after it reaches 
the blood vessels. The reason for this evidently is that in order to 
paralyze the sensory fibres and terminations a considerable amount of 
the drug is required, but much less is necessary to paralyze the central 
nervous system. Even in the frog, the sensory terminations are not 
fully paralyzed until all symptoms of reflex excitability have disap- 
peared and total paralysis has supervened. 

A good deal of discussion has arisen as to whether the action on the sen- 
sory terminations is a specific one, or whether they are paralyzed before the 
motor endings simply because the cocaine comes in contact with them first — 
whether, in fact, if both endings were exposed equally to the action of the 
drug, as occurs when it is distributed by the blood vessels, the sensory ter- 
minations would be specifically attacked and the motor left unaffected. The 
action was at first supposed to be a specific one on the sensory terminations, 
and it was stated that cocaine acted on the sensory terminations in the same 
selective way as curara does on the motor endings. There seems, however, 
to be no ground for supposing that this is the case. At the same time 
cocaine possesses a distinct selective power for the sensory nerve trunks con- 
veying sensations of pain, for when it is injected into the spinal canal, there 
is often complete insensibility to pain while warmth, cold and touch sensa- 
tions are still perceived and the motor functions are unchanged. 

When cocaine is applied locally to a mucous membrane it produces, 
besides a loss of sensation, a feeling of constriction and a distinct pallor 
and contraction of the vessels, which points to a local action on the 
vessel walls. 

The anaesthesia produced by cocaine is comparatively short, but 
varies with the strength of the solution applied and with the vascularity 
of the part; as soon as the cocaine is absorbed, the local action disap- 
pears and sensation returns. 



308 



ORGANIC DRUGS ACTING AFTER ABSORPTION. 



Cocaine is applied to the Eye more frequently than to any other part. 
It produces local anaesthesia here, along with contraction of the con- 
junctival vessels, and this is followed by dilatation of the pupil and 
often by partial loss of the power of accommodation. The dilatation 
of the pupil is much less than that produced by atropine, and differs 
from it in several respects. Thus, the light-reflex is preserved, the 
pupil contracting in bright light and dilating further in the dark ; a 
number of drugs which have little or no effect after atropine, contract 
the cocainized pupil (pilocarpine, muscarine, physostigmine), while 
atropine dilates it still further, and cocaine produces some dilatation 
after the full atropine action has been elicited. It is evident, then, 
that the two drugs produce dilatation by acting on different mechan- 
isms, and although the way in which cocaine dilates the pupil has been 

Fig. 28. 




Diagram of the innervation of the iris. P, a fibre of the motor oculi passing from the brain to the 
ciliary ganglion N, in which it terminates around a nerve cell, which sends an axis cylinder to 
terminate, M, in the circular fibres of the iris. R, a spinal nerve fibre issuing from the lower cervical 
cord, running through the stellate and inferior cervical ganglia and terminating around a ganglion 
cell in the superior cervical ganglion, G. The axis cylinder from this nerve cell runs to the iris ( pass- 
ing the ciliary ganglion) and terminates in fibrils C, on the radiating fibres. C, is the point which 
cocaine stimulates and the resultant contraction of the muscle fibres causes dilation of the pupil, but 
when strong impulses descend to 717, as happens when the eye is exposed to bright light, the circular 
muscle overcomes tbe weaker radiating fibres, and the pupil is contracted. In the same way strong 
stimulation of M by muscarine overcomes the stimulation of C by cocaine, while, on the other hand, 
when M is paralyzed by atropine and the circular fibres are thus thrown out of action, the radiating 
muscles are unopposed, and cocaine causes a greater dilatation than in the normal eye. 



a matter of dispute, the great majority of investigators now hold that 
it stimulates the terminations of the dilator fibres. (Fig. 28.) The 
motor oculi is not involved in its effects, unless very large quantities 
are applied, when its terminations may be depressed in the same way 



COCAINE. 309 

as by atropine (Schultz). A strong argument in favor of the view 
given above has been found in the observation that when the dilator 
nerves degenerate, owing to removal of the superior cervical ganglion, 
cocaine fails to cause dilatation of the pupil. 

Several other symptoms are produced by the local application of 
cocaine to the eye, at any rate in some instances. Thus, the iris ves- 
sels are sometimes much constricted, the eye is more widely open than 
usual, so that the white sclerotic is seen above and below the iris, the 
whole eyeball is pushed forward (exophthalmos), and the intraocular 
tension is said to be considerably reduced. All of these features 
are produced only after cocaine has been applied in considerable quan- 
tity and for some time, and may be due, at any rate in part, to its 
absorption. They may all be observed in the unpoisoned animal when 
the cervical sympathetic trunk is stimulated, and therefore seem to in- 
dicate a special action of cocaine on the centres or terminations of this 
nerve. All of these symptoms, except the anaesthesia and the pallor of 
the conjunctiva and iris, are produced by the injection of cocaine as 
well as by its local application, but in this case are prevented by pre- 
vious section of the cervical sympathetic. Cocaine does not produce 
any dilatation of the pupil in birds. 

Cocaine brought into immediate contact with nerve terminations 
paralyzes them, but this is true for so many other forms of living matter 
that it may be regarded as a General Protoplasm Poison. Thus muscles, 
nerves, and nerve ends cease to contract or to conduct stimuli when 
they are exposed to even very dilute solutions of cocaine ; the ciliated 
epithelial cells, leucocytes, and spermatozoa become motionless ; the 
cortical nerve cells lose their excitability, and many of the inverte- 
brates are killed by even a short exposure to cocaine. The move- 
ments of protoplasm in plants are also retarded or entirely suppressed 
by this poison, and the process of putrefaction is delayed considerably. 
In some cases, notably in the higher invertebrates, the final depression 
is preceded by a stage of increased movement, and it is said that the 
irritability of nerve is also augmented at first. In other instances, 
however, cocaine induces only depression and paralysis. 

Other examples of this destructive action are also seen in the thera- 
peutic use of cocaine, for the cornea is often rendered somewhat 
cloudy from its application, and its subcutaneous injection is sometimes 
followed by necrosis. Victims of the cocaine habit often show nu- 
merous scars on the arms and legs from this local gangrene, although 
this is probably often due to unsterilized syringes rather than to the 
solution. 

Most of the other natural alkaloids resemble cocaine in many points of 
their action, as far as they have been investigated, but some of the artificial 
compounds present divergences from the general type. Thus a number of 
them do not produce anaesthesia, although most of the nearly allied forms 
cause the characteristic changes in the liver cells ; some of them depart en- 
tirely from the typical cocaine action. 

Cocamine is often said to be a cardiac poison, but its action on the heart 
seems to resemble in general that of cocaine. It has, however, a much more 



310 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

intense action on muscular tissue, which it, like caffeine, throws into rigor 
mortis. Its anaesthetic power is very small. 

Benzoylecgonine is a comparatively weak body, which produces symj)toms 
resembling caffeine — increased reflex excitability, muscular stiffness, and 
rigor — and ecgonine is still less active, but elicits in frogs similar effects. 

Some authorities regard the muscular action of caffeine as an important 
factor in its preventing fatigue, and the presence of cocaine in the coca 
leaves might be used to explain the similar effects induced by these, but the 
quantity is probably too small to have any noticeable action. 

Tropacocaine resembles cocaine very closely in its general action, but is 
less poisonous. It produces local anaesthesia more rapidly but for a shorter 
time than cocaine, and causes less dilatation of the pupil. 



Preparations. 

Coca (U. S. P.), the dried leaves of Erythroxylon coca, containing |-1 per 
cent, of cocaine. 

Extractum Cocee Fluidum (U. S. P.), 2-4 c.c. (J-l fl. dr.). 

Extraction Cocse Liquidum (B. P.), \-\ fi. dr. 

Cocaina (B. P.), an alkaloid (C 17 H 21 N0 4 ) obtained from the leaves of 
Erythroxylon coca and its varieties, forming colorless crystals with a bitter 
taste followed by numbness ; insoluble in water, soluble in alcohol. 

Cocainje Hydrochloras (U. S. P.), Cocaine Hydrochloridum (B. P.) 
(C 17 H 21 N0 4 HC1), colorless crystals, very soluble in water and in alcohol ; 
watery solutions cannot be boiled as the alkaloid tends to decompose, 0.01- 
0.06 G. (i-1 gr.). 

Lamellas Cocainse (B. P.), each contains 3V gr. of the hydrochloride. 

Injectio Cocainse Hypodermica (B. P.), 10 per cent., 2-5 mins. 

Unguentum Cocainx (B. P.), 4 per cent. 

Trochisci Kramerise et Cocainse (B. P.), each contains ^ gr. of the hydro- 
chloride. 

The Therapeutic Uses of cocaine are almost all dependent on its an- 
aesthetic action. It has been suggested as a brain stimulant in various 
conditions of mental depression, but has not been widely used for this 
purpose, which is better served by the less dangerous caffeine. A 
wine containing coca extract is often used in domestic medicine as a 
" general tonic," and has repeatedly given rise to the cocaine habit. 

Its anaesthetic properties render it extremely important. In oph- 
thalmic surgery it is used very largely both during operations and to 
alleviate pain, and occasionally to constrict the vessels of the iris in in- 
flammatory conditions. For complete anaesthesia a 4 per cent, solution 
may be employed, while to allay pain one of 1-2 per cent, is all that 
is necessary. The anaesthesia is of short duration, generally setting in 
after 5-7 minutes and passing off 20-30 minutes after the application 
of the drug. Occasionally cocaine, especially in strong solution, pro- 
duces a certain amount of opacity of the cornea, and it is stated that 
wounds heal less readily, and irritant antiseptics are more dangerous 
with cocaine than without it. This may sometimes be due to the use 
of impure cocaine, but it may be noted that cocaine is a protoplasm 
poison, and may therefore lessen the resistance of the tissues with 
which it comes in contact. The usual explanation given that cocaine 
paralyzes sensation in the cornea, and thus prevents the reflex winking 



COCAINE. 311 

which removes foreign bodies from the surface and keeps the eye moist, 
is obviously insufficient, as the anaesthesia is of but short duration. 
The dilatation of the pupil produced by cocaine is much less complete 
than that under atropine, and can only be taken advantage of in diag- 
nosis by using very dim light, as the pupil contracts in bright light 
almost to its normal size. On the other hand cocaine is much less 
injurious in glaucoma and the dilatation can be removed at once by 
the instillation of a few drops of physostigmine. 

In the nose, throat and larynx, cocaine is used in a solution of 4 
per cent., sometimes 10-20 per cent., and anaesthesia is obtained with 
greater difficulty than in the eye, but the local contraction of the ves- 
sels is often of great service. Cocaine is used largely in operative 
procedure here and also in the treatment of irritable conditions of the 
respiratory passages, such as hay fever. In the urethra, rectum and 
vagina, cocaine may also be used either as an anaesthetic or to relieve 
pain temporarily. It is sometimes of service in painful or itching 
skin diseases, but care must be taken not to apply it to large broken 
surfaces, otherwise symptoms of poisoning may follow. The local 
action on the stomach is often valuable in checking vomiting due to 
gastric irritation. 

For many years after its introduction as a local anaesthetic in 1884, 
its use Avas practically limited to minor operations in the nose and 
throat and to ophthalmic surgery, few general surgeons venturing on its 
application in other fields. Within the last few years, however, its use 
has undergone a wide extension, so that almost all the major surgical 
operations have been performed under it and local anaesthesia by means 
of cocaine or eucaine has now become a rival of ether and chloroform. 
Occasionally partial local anaesthesia is combined with the administra- 
tion of small quantities of chloroform or ether, which are insufficient 
to produce complete unconsciousness, but cause a numbing of the 
sensation, which, together with the local action, permits of a painless 
operation. At first strong solutions were injected to prepare the way 
for the knife, each step forward in the operation being preceded by an 
injection of cocaine to induce anaesthesia of the layer of tissue to be 
incised. But this method, which has been used chiefly by Reclus, 
required dangerous quantities of the drug, and is now scarcely used 
except for minor operations in which a single injection is sufficient. 
A more satisfactory method of local anaesthesia for operative purposes 
has been introduced by Schleich under the name of " infiltration 
anaesthesia." A large quantity, sometimes as much as 200 c.c, of a 
solution containing 0.01 per cent. 1 of cocaine and 0.8 per cent, of 
sodium chloride is allowed to permeate the tissues through a fine 
hypodermic needle. Only very slight pressure is required and the 
whole of the surrounding structures become swollen and oedematous 
and can be cut into without pain. Much of the fluid escapes through 
the incisions and no symptoms of poisoning arise. Schleich attributed 
the anaesthesia partly to the pressure exerted by the solution and partly 

1 Some operators use a 0. 1 per cent, solution and then less is injected. 



312 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

to the imbibition, but later investigators have found it to be dependent 
on the cocaine alone. 1 Another method suggested by Oberst is the 
injection of cocaine into the immediate neighborhood of the nerve 
supplying the part to be operated on. Complete local anaesthesia is 
obtained and the absorption may often be prevented or retarded by an 
Esmarch ligature being applied above the point of injection. This 
method has been used extensively in operations on the foot and hand 
for which it is admirably suited. It is difficult to adapt it to other 
parts of the body and it has been generally relegated to the minor 
surgery of the extremities. 

After it was found that the nerve impulses from the periphery to 
the central nervous system could be blocked by the injection of cocaine 
into the peripheral nerves, the next step was to obstruct them higher 
in their course by applying the alkaloid to the spinal roots in the 
vertebral canal. The first to attempt this was Corning of New York, 
but the development of the procedure is due to Bier and Turner. A 
long hollow needle is passed into the spinal canal between the laminae 
of the lumbar vertebrae and 1 c.c. of a 2 per cent', solution of cocaine 
hydrochlorate is injected, after the withdrawal of an equivalent amount 
of cerebrospinal fluid. The actual amount of cocaine injected is thus 
0.02 G. (J gr.). Within a few minutes numbness begins, generally in the 
feet at first, but sometimes in the lower part of the trunk ; it spreads 
upwards rapidly until sensibility to pain is lost everywhere below the 
diaphragm and sometimes in the thorax ; in some cases even the head 
has been found anaesthetized. The sensations induced by warmth and 
cold are less quickly affected, touch is preserved to some extent and 
the limbs can be moved readily, though the movements are carried 
out more slowly than usual ; the consciousness is unimpaired. This 
condition lasts from half an hour to an hour and then sensation 
returns gradually. In the beginning of the action some muscular 
twitching is often seen, and the muscles are never relaxed as they are 
under chloroform or ether. Vomiting occurs in a large proportion of 
cases either during or after the operation, and persistent headache is 
generally present. The cocaine is believed to act on the posterior 
nerve roots and not on the cord itself. The cerebrospinal fluid has 
been found to contain a large number of polynuclear leucocytes after 
the injection and resumes its normal limpid character only after several 
days. This method of anaesthesia has been used in a large number of 
operations, some of them of the gravest nature ; it has also been sub- 
stituted for general anaesthesia in labor. 

Of these methods, Schleich's infiltration has been most widely 
adopted and is admirably suited for minor operations. It is the safest 
method available for most of these, for the amount of cocaine injected 
ought not to be sufficient to induce poisonous symptoms, and should 
never exceed 20 mg. (J gr.) and much of this escapes by the incision. 
It requires some experience to induce complete insensibility to pain by 

1 Heinze showed that the morphine contained in Schleich's original fluid was super- 
fluous. 



COCAINE. 313 

this method and the operation has to be interrupted at intervals to permit 
of further injections. Some headache and nausea are occasional sequelae. 
When general anaesthesia is contraindicated, infiltration may be adopted 
in major operations, while on the other hand it is often contraindicated 
in minor operations where there is any possibility of complications, or 
where the anxiety and nervousness of the patient are likely to interfere 
with the proceedings. Subarachnoid or intraspinal cocainization is 
still on trial, and while it has been enthusiastically praised by some of 
its sponsors, it has in general been regarded as a hazardous method. 
As a matter of fact, no fatality can as yet be certainly affirmed to have 
resulted from it, although it has been employed in over 2000 cases, 
and no permanent injury to the nervous system has hitherto been 
observed from it. It seems probable, however, that it will in the 
future attract less attention than it has recently, and will be regarded 
as a last resort to be used when special circumstances contraindicate the 
general anaesthetics and operation is imperative. 

Cocaine Habit. — Since the introduction of cocaine into general thera- 
peutic use, numerous cases of the formation of a habit similar to that 
of opium or morphine, have been recorded. Some of these have been 
due to the attempt to substitute cocaine for morphine in the treatment 
of chronic morphinism, the treatment often resulting in the develop- 
ment of an irresistible craving for both alkaloids. The symptoms of 
cocainism generally begin with digestive disorders, loss of appetite, 
salivation and emaciation, but the more important changes occur in the 
central nervous system, which apparently undergoes degeneration simi- 
lar to that seen in chronic morphine poisoning. Sleeplessness, tremors 
and occasionally convulsions, hallucinations, insanity and delirium have 
been noted after long abuse, along with indefinite disturbances of sen- 
sation and motion. The treatment of these cases is the withdrawal of 
the drug, and this can generally be done without the production of any 
special symptoms, though it is sometimes followed by great depression. 
This treatment is much facilitated by sending the patient to a special 
resort, and, in fact, is almost hopeless without his isolation. 

Acute Cocaine Poisoning is treated purely symptomatically. Amyl- 
nitrite has been advised when the blood-pressure seems much elevated, 
while for the convulsive attacks small quantities of chloroform or ether 
may be necessary. Of course, the stomach ought to be evacuated 
first of all if the drug has been taken by the mouth. 

Substitutes for Cocaine. 

Some artificial alkaloids have recently been introduced as local an- 
aesthetics instead of cocaine. The best known of these is Beta-eucaine 
(C 1 .H 21 N0 2 ), 1 which is much less poisonous than cocaine and differs 
from it in many points in its general action. In animals poisoned 
with large doses the central nervous system is first stimulated and then 
paralyzed ; the pulse is slowed from direct action on the cardiac mus- 

1 Alpha-eucaine (C^H.^NOJ was formerly used as a substitute for beta-eucaine, but 
induces irritation at first, and is now seldom met with. 



314 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

cle, and the blood-pressure falls. The terminations of the motor nerves 
are paralyzed in frogs, but only after the central nervous system. As 
a local anaesthetic it is almost as efficient as cocaine, and differs from it 
in not constricting the vessels or dilating the pupil. The intraocular 
pressure is said to be lessened, but this is not yet satisfactorily deter- 
mined. A 1-2 per cent, solution of the hydrochlorate is used in the 
eye, 2-5 per cent, for other mucous surfaces and for subcutaneous in- 
jection. Eucaine may be employed in 1 per cent, solution instead of 
cocaine for infiltration anaesthesia, and is less poisonous and can be dis- 
infected by boiling. 

Orthoform is a still more recently introduced local anaesthetic, which 
may be mentioned here, although it resembles cocaine only in its action 
on the sensory terminations. It is the methylester of amidooxyben- 
zoic acid (C 6 H 3 OH(NH 2 ) (COOCH 3 )), and is thus entirely different in 
chemical structure from cocaine. Several other aromatic derivatives 
have long been known to have some numbing or anaesthetic properties, 
but have scarcely been used in therapeutics for this purpose. Even 
carbolic acid has a distinct numbing effect, and some of the antipyretics 
have been proposed for use in ophthalmology. The effects of orthoform 
would therefore seem due to its being an aromatic derivative rather 
than to any relation it bears to cocaine, and Einhorn and Heinz state 
that all esters of amidooxy-acids of the aromatic series have more or 
less anaesthetic action. Orthoform is a white, crystalline powder, which 
has no taste or smell and is only very slightly soluble in water. It 
is used as a dusting powder or in ointment, and is applied to painful 
surfaces, such as abrasions, ulcers or burns, either on the skin or on the 
visible mucous membranes. In ulcer or cancer of the stomach, it has 
also been taken internally, and gives relief from the suffering. It is 
somewhat antiseptic and seems to be practically devoid of poisonous 
properties. It has little or no effect on the sensibility of the unbroken 
skin, and its insolubility precludes its use by subcutaneous injection. 
The anaesthesia begins almost as soon as that induced by ordinary co- 
caine solutions, but lasts very much longer, because orthoform is dis- 
solved and removed from the surface very slowly ; thus a single applica- 
tion of the powder causes anaesthesia for many hours, or even for some 
days. On the other hand, orthoform fails to penetrate the mucous 
membranes as cocaine does, and therefore only anaesthetizes when it 
comes into actual contact with exposed nerve ends. In some cases 
some dermatitis has occurred after the use of orthoform. 

Another series of local anaesthetics has been introduced by Troildenier 
under the name of Acoines. They are derivations of phenylguanidin and 
are said to be much less poisonous than cocaine and to induce complete an- 
aesthesia of the cornea and conjunctiva and also to be available for infiltration 
anaesthesia. Holocaine, a derivative of phenacetine, has been recommended 
in ophthalmological operations, but is more poisonous than eucaine, and 
presents no equivalent advantages. 



Bibliography 

v. Anrep. Pfliiger's Archiv, xxi., p. 38, 1880. 
Mosso. Arch. f. exp. Path. u. Pharm., xxiii., p. 1£ 



i0. 

p. 153. Pfliiger's Archiv, xlvii., p. 553. 



PILOCARPINE AND MUSCARINE. 315 

Alms. Arch. f. Anat. u. Phys., 1886. Supplement, p. 293. 
Kiesow. Wundt's Philosoph. Studien, ix., p. 510. 
Stockman. Brit. Med. Journal, 1889, i., p. 1043. 
Poulsson. Arch. f. exp. Path. u. Pharm., xxvii., p. 301. 
Ehrlich. Deutsch. med. Wochenschr., 1890, p. 717. 

Ehrlich u. Einhorn. Bericht. der deutsch. chem. Gesellsch., 1894, p. 1870. 
Filehne. Berl. klin. Woch., 1887, p. 107. 
Limbourg. Arch. f. exp. Path. u. Pharm., xxx., p. 93. 
Schultz. Arch. f. Anat. u. Phys., 1898, p. 58. 
Danilewsky. Pfliiger's Archiv, li., p. 446. (Invertebrates.) 
Mannheim. Ztschr. f. klin. Med., xviii., p. 380. 
Albertoni. Pfliiger's Arch., xlviii., p. 307. 
Francois- Franck. Arch, de Phys. (5), iv. , p. 562. 
Chadbourne. Brit. Med. Journ., 1892, ii., p. 402. (Tropacocaine. ) 
Vina. Virchow's Arch., cxlv., p. 78. (Eucaine. ) Arch. f. Anat. u. Phys., 1897,, 
p. 163. Virchow's Arch., cxlix., p. 217; cliv., p. 549. 

Einhorn u. Heinz. Munch, med. Woch., 1897, p. 931. (Orthoform.) 

Soidier et Guinard. Arch, internat. de Pharmacodyn., vi., p. 1. 

Wiechowski. Arch. f. exp. Path. u. Pharm., xlvi., p. 154. 

Heinze. Virchow's Arch., cliii., p. 466. 

Biberfeld. Arch, internat. de Pharmacodyn., vi., p. 385. 

Trollclenier. Therap. Monatsh., 1899, p. 36. (Acoines.) 

Braun. Arch. f. klin. Chir., lvii., p. 370. 

Gottstein. Ibid., lvii., p. 409. 

Mikulicz. Ibid., lxiv., p. 757. 

Bier. Ibid., lxiv., p. 236. 

Lea. Journ. of Obstet. and Gynecol., i., p. 71. 

Terreit. American Medicine, 1901, ii., p. 417. 

XV. PILOCARPINE AND MUSCARINE. 

Pilocarpine and muscarine, two alkaloids of very different chemical 
constitution, possess similar properties from a pharmacological point of 
view. Pilocarpine (C 11 H 16 1^ 2 2 ) 1 is found along with Isopilocarpine in 
the leaves of several species of Pilocarpus. 

Muscarine, the alkaloid of one of the poisonous mushrooms, Agari- 
cus muscarius, is a derivative of the methane series, very closely re- 
lated chemically to choline, which is a constituent of several animal 
tissues. Its exact constitution is somewhat doubtful, but it may prob- 
ably be represented by the formula 

CH-(OH) 2 

CH— N(CH 3 ) 3 OH 

It occurs in the mushroom associated with cholin, and sometimes 
apparently with a base which acts like atropine. A substance almost 
identical with muscarine from the chemical standpoint has been pre- 
pared by the oxidation of cholin, but this synthetic muscarine differs 
in its action from the natural alkaloid in several respects. A number 
of other nearly related bodies (trimethylammonium bases) resemble 
muscarine in some points of their action, but are not so poisonous, and 
fail to act on several of the organs affected by the base derived from 
the mushroom. 

1 The structural formula of pilocarpine is not yet definitely determined. Pilocarpi- 
dine has been isolated from the leaves of Pilocarpus Jaborandi only and is practically 
inert. Jaborine was formerly stated to occur with pilocarpine and to possess an action 
resembling that of atropine, but more recent investigators have failed to confirm either 
of these statements. 



316 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

Muscarine, pilocarpine and isopilocarpine resemble each other in 
action ; muscarine is much more poisonous than pilocarpine, which is 
again eight times as active as isopilocarpine. 

Pilocarpine and muscarine stimulate the terminations of certain 
nerves supplying unstriated muscle (except that of the vessels), the 
heart and secretory epithelium. Their effects are therefore diametri- 
cally opposed to those of atropine in the peripheral organs. 

Symptoms. — The symptoms of poisoning in man commence with a 
very marked secretion of saliva, followed soon after by excessive per- 
spiration and a flow of tears. After muscarine and sometimes after 
pilocarpine, nausea, retching and vomiting, pain in the abdomen and 
violent movement of the intestines causing profuse watery evacuations, 
are next observed. The pulse is sometimes quickened, sometimes very 
slow and irregular ; the pupil is contracted, and the sight is accommo- 
dated for near objects. The respiration is often quick and dyspnoeic, 
and rales may be heard over the bronchi, denoting an accumulation of 
mucus in them. Giddiness and confusion of ideas are complained of, 
and after pilocarpine tremors and feeble convulsive movements are 
sometimes observed, but the nervous symptoms are not so conspicuous 
as those from the peripheral organs. Eventually the respiration be- 
comes slower and great weakness in the movements manifests itself, 
but the consciousness remains more or less perfect till the breathing 
ceases. 

Action. — The salivary and lachrymal Glands, the mucous glands of 
the mouth, throat, nose and deeper respiratory passages, the gastric 
secretory glands, the pancreas, and probably the intestinal glands, all 
secrete copiously after muscarine and pilocarpine. The sweat glands 
and the ceruminous glands of the ears are likewise roused to unwonted 
activity, and many other glandular structures are also stimulated. 1 

In most cases the solids of the secretions are increased as well as 
the fluids, although to a somew r hat less extent. The bile, the urine 
and the milk do not seem to be affected directly by pilocarpine and 
muscarine, although they may be reduced in amount or otherwise 
modified by the withdrawal of large quantities of fluid from the body 
by other channels. 

After a small quantity of atropine, pilocarpine and muscarine in 
ordinary quantities produce no increase in any of the secretions. This 
indicates that the seat of action of these poisons is not the secretory 
cells, for it has been shown that atropine paralyzes only the termina- 
tions of the secretory nerves and leaves the cells uninjured. On the 
other hand, section of the secretory nerves does not alter materially 
the action of pilocarpine or muscarine, for the secretion of perspira- 
tion in the foot of the cat is increased by pilocarpine even after section 
of the sciatic nerve. The seat of action of pilocarpine and muscarine 
is therefore the terminations of the secretory nerves — the minute fibrils 
which ramify between the epithelial cells and perhaps even enter them. 

1 A curious example of this has been shown by Dreser to occur in the fish, in which 
the swimming bladder secretes more oxygen than usual. 



PILOCARPINE AND MUSCARINE. 317 

These fibrils are stimulated by the members of this group aud para- 
lyzed by atropine, aud these two series therefore form antidotes to one 
another. 

The salivary secretion may amount to half a litre or more in the 
course of 2-3 hours after an injection of pilocarpine, while the skin 
and lungs excrete even a larger quantity of fluid in the same time. 
The weight is thus considerably reduced by pilocarpine owing to the 
loss of fluid, which may, according to some authors, amount to 2-4 
kilogrammes (4J— 9 lbs.) after a single dose. 

The secretion of the milk is not increased by pilocarpine, but the 
percentage of sugar in it is stated to be larger than usual. The 
sugar of the blood has been found increased by pilocarpine, and this 
has been attributed to its acting on the terminations of the nerves in 
the liver which regulate the glycogenic functions of that organ. 

The increased activity of the glands is accompanied by an accelera- 
tion of the blood current through them, but this is a result of their 
stimulation from any cause whatever, and is probably not due to the 
direct action of the alkaloids on the vessels. The redness of the skin, 
especially of the face, so often observed after pilocarpine, may perhaps 
be explained in this way, as an accompaniment of the augmented ac- 
tivity of the sweat glands. 

It was formerly supposed that pilocarpine acted on the same structures as 
nicotine — the sympathetic ganglia — but this is disproved by the sweat secre- 
tion of the foot after section of the sciatic, for no sympathetic ganglia have 
been found in connection with these sweat glands except those in the pelvis. 
Another question which has been the subject of prolonged and somewhat 
bitter discussion is whether pilocarpine and muscarine can act at all after 
atropine. It seems now to be admitted that while minute quantities of 
the latter stop secretion set up by ordinary doses of pilocarpine and mus- 
carine, yet either of these in very large quantities will reinstate it, and this 
alternation of stimulation and depression may be repeated a number of 
times. 

After a prolonged stage of stimulation large quantities of pilocarpine or 
muscarine eventually paralyze the nerve terminations, and the secretions are 
therefore diminished or stopped entirely. But this never occurs save in ex- 
periments on animals, for, as a general rule, the respiration is paralyzed by 
smaller quantities than are necessary to elicit this feature. 

Muscle. — Nausea and discomfort in the stomach, followed by retch- 
ing and vomiting, are rarely seen after pilocarpine, but form some of 
the earliest symptoms of muscarine poisoning. They are not produced 
by the saliva swallowed, as was formerly supposed, but by a stimula- 
tion of the terminations of the pneumogastric in the muscular coats of 
the stomach, similar to that of the terminations of the secretory nerves. 
This is, perhaps, incapable in itself of producing complete evacuation 
of the stomach, but may set up a reflex contraction of the muscles of 
the abdominal wall which accomplishes it. 

The intestines are also set in unusually active movement by a similar 
process, and repeated evacuation of their contents follows. These 
are at first of firm consistency, but later, as the continued peristalsis 



318 ORGANIC DRUGS ACTING AFTER ABSORPTION 

carries down the contents of the small intestine, which have not lain 
long enough in the bowel to allow of the absorption of their fluid, the 
faeces contain more water than usual. This fluidity of the stools may 
also be due in part to an augmentation of the intestinal secretion, but 
this has not been satisfactorily demonstrated. Even after the bowel 
has been completely evacuated, the persistent peristalsis betrays itself 
in painful straining. 

The muscle of a number of other organs contracts after pilocarpine 
or muscarine, also, it is believed, from stimulation of the nerve ter- 
minations. Thus the spleen, bladder, bronchial muscles, and possibly 
the uterus, are contracted, and in the case of the bladder repeated 
evacuation and straining may occur. Of much greater importance 
than these is the effect of pilocarpine and muscarine on the eye. In 
poisoning with these and also on local application, the pupil becomes 
extremely narrowed, and at the same time the ciliary muscle contracts 
so that the lens is accommodated for short distances. Both of these 
phenomena are due to stimulation of the terminations of the motor 
oculi in the intraocular muscles (see Fig. 26, p. 287) ; they are not 
equally easily elicited, however, for according to Krenchel, muscarine 
acts on the ciliary muscle much more readily than on the pupil, so that 
occasionally the sight may be accommodated for short distances while 
the pupil remains fairly wide. The intraocular pressure is reduced by 
muscarine and pilocarpine, although they may increase it at first. 
This has not been explained, but is often said to be associated with the 
changes in the pupil, myosis (contraction of the pupil) being generally 
attended by a reduced tension. The stimulant action of pilocarpine on 
the terminations of the motor oculi terminates in depression and con- 
sequent slight widening of the pupil. 

All these muscular phenomena are prevented by the previous ad- 
ministration of atropine. This antagonistic action has been carefully 
studied in the eye, where it is found that after pilocarpine has pro- 
duced contraction of the pupil, the administration of very small quan- 
tities of atropine is followed by dilatation. Strong pilocarpine solution 
again dropped into the eye will again reduce the size of the pupil, but 
the quantity required is vastly more than in the normal eye, and this 
second contraction may again be removed by comparatively small 
quantities of atropine. In the bird's pupil, in which the muscle is 
striated, muscarine and pilocarpine have no eifect, the terminations of 
the nerves being evidently different from those in mammals. 

The action of pilocarpine and muscarine on the Circulation presents 
some differences in different species of animals. On the applica- 
tion of either to the frog's heart, its rhythm is at once slowed, the 
diastolic pause being much increased in length and the contractions 
lessened in force. Soon the heart ceases to beat entirely, although 
irritation of its muscle by mechanical or chemical means elicits one or 
more contractions. A number of drugs which stimulate the heart 
muscle, such as physostigmine or digitalin, induce weak rhythmical 
contractions, but atropine in the minutest quantities restores the heart 



PILOCARPINE AND MUSCARINE. 



319 



to its normal rhythm and strength. The symptoms produced are ex- 
actly those seen on stimulation of the vagus by electrical shocks, and 
muscarine has long been believed to act by stimulation of the inhibi- 
tory mechanism in the heart. It is generally stated that the site of 
its action is the ganglia on the course of the vagus, but this is incor- 
rect, for muscarine acts on the apex of the frog's ventricle, in which 
no ganglia whatever have been found. Muscarine, therefore, stimu- 
lates the terminations of the vagus fibres in the heart muscle, and 
thus produces slowing and eventually standstill. Atropine removes 
this standstill by paralyzing the terminations, but larger quantities of 
muscarine or pilocarpine will again overcome the atropine action and 
restore the standstill or, at any rate, the slow pulse. Physostigmine 
and digitalin remove the standstill by increasing the irritability of the 
muscle until the inhibition can no longer hold the heart in check, but 
throughout the rhythm caused by these the activity of the vagus can 
be seen in the slowness of the beat and the prolongation of the diastole. 
The vagus ends are eventually paralyzed by pilocarpine and the heart 
resumes its normal rate. Larger quantities, however, again slow it 
owing to direct action on the cardiac muscle. 

In rabbits and cats similar changes are seen in the circulation after 
muscarine. The heart is slowed or brought to a complete standstill, 



Fig. 29. 




AJJdMJ 



B A 





Tracings of the movement of the auricle Cupper) and ventricle (lower) of the dog under muscarine. 
During contraction the levers move upwards ; during relaxation downwards. A-B, normal. At B, 
muscarine was injected intravenously and at Cit began to act. The movements of the ventricles are 
slower and a distinct pause is seen in diastole. The contraction is less complete, while the heart 
relaxes more than usual during diastole. The auricle soon comes to a standstill in diastole. Com- 
pare the effects of stimulation of the vagus in the first part of Fig 27, page 289. 

the blood pressure falls, and all the symptoms produced by anaemia 
of the brain may follow, but the animal becomes again perfectly nor- 
mal on the administration of small quantities of atropine. The fall in 
blood-pressure is often greater than is accounted for by the slowing of 
the heart, and the peripheral vessels are extremely congested. This 



320 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

may possibly be due to the dilatation of the vessels which, as already 
stated, accompanies the increased activity of the glands. Pilocarpine 
differs from muscarine here in several particulars, for it soon depresses 
the inhibitory fibres and the heart regains its former rhythm, but the 
cardiac muscle is then affected, so that the contractions rapidly be- 
come weaker and slower again, and this- secondary slowing is not re- 
moved by atropine ; the vaso-motor centre also becomes gradually 
weakened by large doses, so that the blood vessels remain somewhat 
dilated, and the arterial tension remains low even after atropine. 

In dogs, the stimulation of the inhibitory fibres seems sometimes to 
be entirely absent after pilocarpine and muscarine, and in man this is 
very frequently the case. Instead of a slow pulse and lessened ten- 
sion in the arteries, acceleration and increased blood-pressure are then 
observed. This is accompanied in man by marked palpitation and 
discomfort in the region of the heart and by dilatation of the skin 
vessels, especially of those of the face. In other cases, however, the 
same circulatory disturbances are produced as in the cat and rabbit. 
(Fig. 29.) No explanation of the acceleration of the heart has been 
offered, but Howell has found acceleration constantly produced by mus- 
carine in the crab's heart. 

In embryo hearts, muscarine, in ordinary quantities, produces no 
change whatever during the first 150 hours of life (in the chick). The 
explanation of this phenomenon is that the inhibitory nerves have not 
been developed at this stage, and after their development is complete, 
muscarine acts on the heart as in the adult. The absence of slowing 
in some of the invertebrates may be due to a similar cause, although 
this does not held good for the crab, in which there is a well-defined 
inhibitory apparatus. 

The Respiration is unaffected by small quantities of the members of 
this series except indirectly through the changes in the circulation, 
which lessen the amount of blood passing through the lungs and there- 
fore produce asphyxial dyspnoea. Large quantities of pilocarpine cause 
a tendency to convulsive movements and a more rapid and labored 
respiration. Eventually the respiration becomes slow and weak and 
asphyxia follows. 

Occasionally oedema of the lungs occurs in animals poisoned by mus- 
carine or pilocarpine. This is more especially the case in cats and rab- 
bits, and seems to be associated with the inefficiency in the circulation 
in the lungs rather than with the stimulation of the bronchial secretory 
glands. It has also occurred in cases of fatal poisoning in man. 

It has been found that pilocarpine increases the Leucocytes of the 
blood, and this is generally attributed to its acting on the tissues which 
form leucocytes, an explanation which is supported by the statement 
of Ruzicka, that the Malpighian corpuscles of the spleen are increased 
in number after pilocarpine. The leucocytosis leads to an augmenta- 
tion of the uric acid in the urine. 

The Temperature is often said to be increased by pilocarpine, although 
only to a very small extent, but this has been shown to occur only 



PILOCARPINE AND MUSCARINE. x321 

when the thermometer is applied to the skin, and to be absent when 
the rectal temperature is taken. The explanation, therefore, seems to 
be the increased blood flow in the skin, which has been already men- 
tioned. After the perspiration is fully developed the internal tem- 
perature is generally reduced, especially in fever. 

Some symptoms occur in cases of poisoning which point to some 
action of the alkaloids on the Central Nervous System. Thus frogs 
develop well-marked convulsions, and even in the higher animals and 
man tremor and slight convulsive movements, such as hiccough, have 
been observed. In the later stages muscular weakness is developed, 
and the slow respiration and the fall in blood-pressure also indicate a 
central action, which seems to be confined to the lower parts of the 
nervous system, however, for consciousness remains little altered. 
These symptoms may be complicated by marked convulsions which 
appear to be due to the anaemia of the brain and do not denote any 
direct action on that organ. 

Pilocarpine and muscarine, while resembling each other in general, 
present some points of difference, which are of the greatest importance 
as regards their use in therapeutics. Muscarine has practically never 
been introduced into medical practice, because, while its action on the 
secretions is quite equal to that of pilocarpine, the gastric symptoms 
are produced much more readily by it. It is also a very much more 
powerful poison than pilocarpine, and is much less easily prepared in 
pure form. 

Prepaeations. 
(Muscarine is not used in therapeutics.) 

Pilocarpus (XL S. P.), Jaborandi Folia (B. P.), the dried leaflets of Pilo- 
carpus Jaborandi l (and of P. Selloanus, U. S. P.). 

Extractum Pilocarpi Fluidum (XL S. P.), \—1 c.c. (8-30 mins.). 

Extractum Jaborandi Liquidum (B. P.), 5-15 mins. 

Tinctura Jaborandi (B. P.), J-l fl. dr. 

Pilocarpine Hydrochloras (U. S. P.) (C n H 16 N 2 2 HCl), the hydro- 
chlorate of an alkaloid obtained from Pilocarpus, forms small, white crys- 
tals, odorless, with a slight bitter taste, deliquescent in the air, very soluble 
in water and alcohol. 0.003-0.03 G. (2W gr.)- 

Pilocarpine Nitras (B. P.) (C 12 H 16 N 2 2 HN0 3 ), the nitrate of an alka- 
loid obtained from Jaborandi leaves, forms a white crystalline powder, which 
is soluble in 8-9 parts of cold water, and is freely soluble in hot alcohol. 
h-h gr. 

The preparations of the crude drug are but little used, as they vary greatly 
in their activity and cause nausea and vomiting more readily than the alka- 
loidal salts. This is explained by the fact that they are absorbed more 
slowly from the alimentary canal, and therefore have longer time to produce 
their characteristic effects upon it. 

Therapeutic Uses of Pilocarpine. — Its action on the sweat glands 
renders pilocarpine much the most powerful diaphoretic in the pharma- 
copoeia, and it is used internally almost exclusively for this purpose. 
In various conditions in which excess of fluid accumulates in the body, 

1 Pilocarpus jaborandi leaves are now extremely scarce and have been supplanted 
by those of Pilocarpus pinnatifolius and P. microphyllus. 
21 



322 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

pilocarpine may be exhibited to remove it. In dropsy, especially that 
due to renal disease, a few injections frequently reduce the fluid and 
remove the effects of the accumulation, although they do not, of course, 
affect the diseased tissues directly. By unburthening the blood and 
tissues of their excessive fluid, however, pilocarpine may improve the 
nutrition of the kidney, and thereby promote its recovery. In dropsy 
due to heart disease pilocarpine must be used with caution, owing to 
its exercising a depressant action on the circulation, perhaps on the 
heart itself. In some other pathological exudations pilocarpine has also 
been advised, as in pleural, pericardial and subretinal effusion. It must 
be remembered that after the diaphoresis produced by pilocarpine there 
usually sets in a period of depression, weakness and languor, and this 
may be sufficient to counteract the improvement obtained by the re- 
moval of the fluid. It is still a disputed point whether pilocarpine 
possesses any advantage as a diaphoretic over the other means of pro- 
ducing sweating, such as hot or cold packs. Its advocates point to 
the fact that much less disturbance of the patient is required, and that 
the subsequent depression is not greater, while its opponents assert 
that the hot or cold pack produces less depression and is not accompa- 
nied by the unpleasant salivation and occasional nausea of pilocarpine. 
Accumulations of fluid in the body may also be removed by way of 
the bowel by the use of a hydragogue cathartic or preferably a saline 
purgative, or the kidney may be stimulated to special activity by the 
use of such diuretics as theobromine and caffeine. The last method of 
treatment is that generally preferred as it induces less weakness and 
depression subsequently than either of the others. 

In uraemia pilocarpine sometimes proves of great benefit if exhibited 
early, and it has been supposed that this was due to the skin taking 
up the renal function vicariously and eliminating the poison. Some 
support has been given this explanation by the discovery of traces of 
urea in the perspiration after pilocarpine, but it is now recognized that 
the urea is not the poisonous j>rinciple in uraemia, and the beneficial 
effects are probably due rather to the removal of fluid and the relief 
of the overstrained circulation. It has also been suggested that pilo- 
carpine acts directly on the kidney, and an increase in the urine is not 
infrequently seen after several injections ; but this is to be ascribed 
rather to the changes in the circulation following the removal of the 
fluid than to any direct action on the renal epithelium, for which there 
does not exist any satisfactory experimental evidence. 

Pilocarpine has been used in a number of fevers and in diphtheria 
and syphilis, but no sufficient evidence of improvement in those con- 
ditions has been brought forward. 

In ophthalmic surgery pilocarpine has been employed as a substi- 
tute for physostigmine, to contract the pupil and reduce the intraocular 
pressure. For this purpose a very dilute solution of the salts (2 per 
cent.) may be used, or lamellae of gelatin may be prescribed, each con- 
taining \ mg. (2^0" £ r, )> *° ^ e ^ a ^ on * ne C0n j unc tiva. The contraction 
of the pupil generally attains its maximum in about J— 1 hour, and 



PILOCARPINE AND MUSCARINE. 323 

passes off in 3-5 hours ; it is generally less complete and of shorter 
duration than that seen after physostigmine. Pilocarpine first in- 
creases and then lowers the intraocular tension. 

In various diseases of the ear, pilocarpine has been used with good 
effects in some cases, but it is quite unknown how it acts here. The 
conditions in which it is of service are various forms of labyrinthine 
disease, and some forms of effusion into the tynipanic cavity. 

Pilocarpine was at one time recommended us an ecbolic l and several 
cases of abortion have been ascribed to its use. Further experience 
has led to the conclusion, however, that if it possesses any action 
whatsoever on the pregnant uterus it only does so when administered 
in quantities which produce undesirable secondary symptoms. 

Pilocarpine is frequently prescribed in lotions for the hair, and a 
renewed growth of the hair has been frequently seen in alopecia treated 
in this way. This has been explained by its action on the glands of 
the skin, increasing the moisture of the scalp and improving its circu- 
lation and nutrition, but Tappeiner found that the local application 
of pilocarpine to the skin produced no increase in the secretion of the 
glands. 

In cases of atropine poisoning, large doses of pilocarpine have been 
ordered with alleged good results. In animal experiments, however, 
the quantity of pilocarpine necessary to antagonize even small doses of 
atropine has been found to be so large that there is little reason to 
hope for improvement from its administration in poisoning in man, 
especially as the action of atropine on the central nervous system is 
not antagonized by pilocarpine. In poisoning from pilocarpine or 
muscarine small quantities of atropine are the antidote recommended 
alike by pharmacological experiment and by clinical experience. 

Muscarine Intoxication. — In Siberia the Agaricus muscarius is used 
to form an intoxicating beverage. The symptoms produced are hilarity 
and jollity, and the victims declare themselves to be more capable 
of fatiguing exertions than they would be without the preparation. 
Eventually giddiness and somnolence are produced, and after large 
quantities vomiting and convulsive attacks may follow and eventually 
prove fatal. The absence of marked symptoms of poisoning in those 
people seems due to a tolerance having been produced by frequent use 
of the drug, for a similar result is seen in the absence of symptoms of 
nicotine poisoning in habitual smokers. 

Bibliography. 2 
Muscarine. 

Schmiedeberg u. Koppe. Das Muscarin. Leipzig, 1869. 
Prevost et Monnier. Gaz. med. de Paris, 1874, p. 243. 
Krenchel. Arch. f. Ophthalm., Bd. xx., p. 135. 
Seth Jordan. Arch. f. exp. Path. u. Pharm., viii., p. 15. 

1 An ecbolic is a drug used to evacuate the contents of the uterus. 

2 The literature of muscarine and pilocarpine is so mixed, with that of atropine, nico- 
tine and physostigmine, that a complete list would involve numerous repetitions. I 
must, therefore, refer those interested to the bibliography given under those groups, 
and shall mention here only the papers which deal very largely with muscarine and 
pilocarpine. 



324 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

Harwich. Ibid., iv., p. 168. 

Schmiedeberg u. Harnack. Ibid., vi., p. 101. 

Trurnpy u. Luchsinger. Pfliiger's Archiv, xviii., pp. 501, 587 ; xv., p. 482. 

Hammerbacher. Pfliiger's Archiv, xxxiii., p. 228. 

Robert Arch. f. exp. Path. u. Pharm., xx., p. 92. 

Cushny. Ibid., xxxi., p. 432. 

Krehl u. Romberg. Ibid., xxx., p. 49. 

Ringer. Journ. of Phys., iii., p. 115. 

Gas/cell. Phil. Trans. Rov. Soc, 1882. Journal of Physiol., iii., iv., viii. 

Weinzweig. Arch. f. Anat. u. Phys., 1882, p. 527. 

Grossmann. Ztschr. f. klin. Med., xii., p. 550. 

Nothnagel. Berichte der Berl. Chem. Gesellsch., 1893, i., p. 801. 

Horbaczewski. Sitzungsher. d. Wiener Akad., 1891. 

Ruzicka. Allgem. Wien. med. Zeitung, 1893, p. 345. 

Schultz. Arch. f. Anat. u. Phys., 1898, p. 73. 

Pilocarpine. 

Langley. Journ. of Anatomy and Physiol., x., p. 187. Journ. of Physiol., i., iii. 
Cf. Nicotine. 

Luchsinger. Pfliiger's Archiv, xv., p. 482 ; xviii., p. 501. 

Lewin. Charite-annalen, v., p. 489. 

Kakler u. Soyka. Arch. f. exp. Path. u. Pharm., vii., 435. 

Pit icier. Dissertation, Bern, 1875. 

Ringer and MurreU. Journ. of Physiol., ii., p. 135. 

Albertoni. Arch. f. exp. Path. u. Pharm., xi., p. 415. 

Nawrocki. Central b. f. d. med. Wissensch., 1878, p. 97. 

Harnack u. Meyer. Arch. f. exp. Path. u. Pharm., xii., p. 366. 

Harnack. Ibid., xx., p. 439. 

Ringer. Practitioner, xxvi., p. 5. 

Scldegel. Arch. f. exp. Path. u. Pharm., xx., p. 271. 

Schiff. Archiv f. Verdauungskrh., vi., p. 107. 

Marshall and Jowett. Brit. Med. Journ., 1900, Oct. 13th. 

XVI. PHYSOSTIGMINE. 

Physostigmine or Eserine is the chief alkaloid of the Calabar bean, 
or Ordeal bean (Physostigma venenosum), which grows in Western 
Africa and was employed there by the natives in the trials by ordeal 
for witchcraft. Either physostigmine itself, or a nearly allied alkaloid, 
occurs also in the Kali or Cali nuts, the seeds of Mucuna urens. The 
constitution of physostigmine (C 15 H 2l N 3 9 ) is still unknown. Two 
other alkaloids have been found in the extract of the Calabar bean and 
are probably products of the decomposition of physostigmine, which is 
a very unstable body. These are Calaba? % ine, which resembles strych- 
nine in its effects, and Eseridine, which acts in the same way as physo- 
stigmine, but is much less poisonous. 

Physostigmine produces a number of symptoms resembling those of 
muscarine and pilocarpine poisoning, and many authors describe all 
three together, but it departs in certain points from the type of these 
two drugs, and according to one theory acts upon a different set of 
tissues. 

Symptoms. — The symptoms of poisoning vary but little in different 
animals ; in the dog and rabbit the first results of a large dose of 
physostigmine are weakness in the voluntary movements and a curious 
tremor and muscular twitching, beginning in the hind legs, but soon 
extending over the whole body. The animal falls on one side and can 
not raise itself again, although it makes efforts to do so when touched. 



PHYSOSTIGMINE. 325 

The saliva and tears are increased, the bowel is often evacuated and 
in the dog vomiting is common. The respiration is at first rapid 
and deep, and later slow and dyspnoeic, the heart is weak and slow, 
and the pupil is contracted to a small point. These symptoms become 
more marked as more of the poison reaches the blood, until the respira- 
tion ceases. In cats these symptoms of depression and paralysis are pre- 
ceded by a stage of increased movement and evident anxiety, but the 
later symptoms resemble those in the dog. In man physostigmine elicits 
practically the same results as in the dog, vomiting and pain in the 
stomach region, dyspnoea, giddiness and muscular weakness, contrac- 
tion of the pupil, salivation and perspiration. The heart is slow, 
muscular twitching may be present and complete collapse follows. In 
frogs the voluntary movements disappear soon after the injection of 
physostigmine, the respiration ceases, and last of all the reflexes are 
paralyzed. 

Action. — Many of these symptoms evidently arise from depression 
of the Central Nervous System, and the cause of death is the failure of 
the respiration from paralysis of the medullary centre. Some doubt 
exists as to what parts of the nervous system first undergo depression. 
Thus according to Harnack and Witkowsky, the higher centres are 
weakened earlier than the lower ones, but in man at any rate, the 
consciousness remains unimpaired after grave derangement of the 
respiration has manifested itself and after the muscular power is con- 
siderably depressed. This would indicate that some of the higher 
cerebral areas preserve their functions after others have been weakened, 
and several authors have therefore maintained that the depression 
commences in the cord and medulla oblongata, and only spreads to the 
cerebrum after large doses. 

Another unsettled question is whether the stage of depression is preceded 
by one of direct stimulation of the nervous centres. Some symptoms un- 
doubtedly point to an increase in their irritability ; for example the increased 
respiratory movements, and to some extent the changes in the blood-pressure 
can scarcely be explained save by stimulation, direct or indirect. 

Further evidence of the stimulant action of physostigmine on the central 
nervous system has been offered by its effects in epileptics, in whom the 
number and intensity of the seizures are increased by its use. Guinea- 
pigs rendered epileptic by operative procedures are also said to be more 
frequently attacked when physostigmine is exhibited, and even in the dog 
epileptiform convulsions occur occasionally, while in the cat a stage of 
excitement is a regular precursor of the depression. These symptoms have 
been explained by some writers as due to stimulation of the central nervous 
system, but, on the other hand, may be due to the peripheral effects of the 
poison, such as the constriction of the air passages by contraction of the 
bronchial muscles. The question as to whether any general stimulation of 
the central nervous system occurs in physostigmine poisoning must be left 
open for the present. 

The muscular twitching seems to be entirely independent of the 
central nervous system, for it is not prevented by division of the motor 
nerves. This symptom is not marked in frogs, but may be so devel- 
oped in mammals as to simulate convulsions, and is due to stimulation 



326 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

of the nerve terminations in the muscles, for it is prevented by curara, 
which paralyzes these. The antagonism between these two alkaloids is 
mutual, for the paralysis of the motor nerves induced by curara may 
be removed by physostigmine applied in somewhat large doses, and 
animals may thus be recovered from quantities of curara which would 
otherwise prove fatal. 

The Respiration is at first somewhat accelerated and then becomes 
slow and weak. The preliminary acceleration was explained by 
Bezold and Gotz as due to stimulation of the sensory terminations in 
the lungs, while others regard it as evidence of central stimulation. 
The subsequent weakness and slowness of the breathing is undoubtedly 
of central origin, and death follows from the failure of the respiratory 
centre. 

The changes in the Circulation require further investigation. 
Small doses slow the pulse and increase the blood-pressure, while 
larger are followed by greater slowing of the heart and a fall in 
the blood-pressure. The slowness of the pulse is due to the poison 
acting on the heart directly and not to any inhibitory interference, for 
it occurs after large quantities of atropine. The action of physostig- 
mine on the inhibitory nerves has never been satisfactorily decided, for 
according to some authors they are unaffected, while others assert that 
their irritability is increased, and Arnstein and Sutschinsky even state 
that the paralyzing effects of atropine may be removed by it. The con- 
tractions of the mammalian heart are sometimes said to be strengthened 
by physostigmine, but this is erroneous ; the increased amplitude of 
the movements mentioned by Hedbom may be due to the slow 
rhythm. 

The increased blood-pressure has also been the subject of some dis- 
cussion. It seems independent, in part at least, of the vaso-motor 
centre, for it is not prevented by section of the spinal cord or of the 
splanchnic nerves, operations which prevent impulses from the centre 
reaching the vessels. It may be partly due to the powerful contrac- 
tion of the intestines expelling the blood from the mesenteric area, or 
to direct action on the muscular coats of the arterioles causing con- 
traction and thus narrowing their calibre, or perhaps to both of these, 
along with some increase in the activity of the vaso-motor centre. 

The frog's heart beats more slowly after physostigmine, but here 
the individual contractions are said to be strengthened and prolonged, 
and there is definite evidence of stimulation of the heart muscle, which 
is not seen in mammals. If the vagus be stimulated in the frog after 
physostigmine, it produces slowing but no complete standstill of the 
heart, because the irritability of the muscle is so much augmented that 
the inhibitory apparatus can no longer entirely control it. It has been 
supposed that physostigmine depresses the endings of the inhibitory 
nerves, but this has been shown to be incorrect. If such a poison as 
muscarine produces complete standstill, physostigmine removes it, not 
by inducing depression of the inhibitory apparatus, but by ^increasing 
the irritability of the muscle. 



PHYSOSTIGMINE. 



327 



The following experiment, which is mainly a repetition of one devised by 
Harnack, may serve to show the relationship between the effects of a whole 
series of poisons, which generally present some difficulties to the student. 
A frog, with brain and spinal cord destroyed, is stretched on a board, and 
its heart is exposed by the removal of a triangular piece of skin and division 
of the sternum. The poisons are then applied in succession by injecting 
them into the lymph sac, and the vagus may be exposed and placed on elec- 
trodes. 

The injection of nicotine causes slowing of the heart (Fig. 30, N), followed by 
a return to the normal rhythm, after which vagus stimulation has no effect, 
while stimulation of the sinus still slows the heart. (Nicotine first stimu- 
lates and then paralyzes the ganglia on the course of the inhibitory fibres.) 
Muscarine now brings the heart to a standstill (Fig. 30, M), through stimu- 
lation of the terminations of the inhibitory fibres in the muscle. Physostig- 
mine restores the heart to feeble rhyihmic contractions (Fig. 30, P), through 
stimulation of the muscular fibres, which leads to a partial loss of control 
by the inhibitory apparatus. Copper salts or other muscular depressants 
cause a return of the standstill (Fig. 30, C), through neutralizing the stimu- 
lant action of physostigmine, and thus allowing the stimulated inhibitory 
endings to regain control. Atropine finally induces an almost complete 
return to the normal rhythm (Fig. 30, .4) by paralyzing the terminations of 
the inhibitory nerves and thus removing the effects of the muscarine. 

Here there is distinct evidence of an increase in the irritability of the car- 
diac muscle of the frog after physostigmine, and this is difficult to reconcile 
with the slow pulsation generally seen when physostigmine is given alone. 
In the mammalian heart no such evidence of an increase in the muscular 
irritability has been adduced, and the vagus arrests it as easily as before the 
administration of the poison ; according to some investigators even more 
easily. 

Fig. 30. 




<rv 



Tracing of the movements of the frog's ventricle. During systole the lever makes an up-stroke. 
Z. Normal, .V. After nicotine. M. After muscarine. P. After physostigmine. C. After a copper 
salt. A. After atropine. (See text.) 

Physostigmine produces powerful contractions of the Stomach and 
Intestine exactly resembling those elicited by muscarine and pilo- 



328 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

carpine. It differs from these, however, in causing these move- 
ments after small quantities of atropine, while larger doses of atropine 
again stop the contractions set up by physostigmine. 

The Secretions are also increased by physostigmine as by pilocarpine 
and muscarine, and here again small quantities of atropine do not 
prevent the action, while larger quantities arrest it. Thus, the saliva, 
the tears, the perspiration, the mucous secretions and the pancreatic 
juice are all augmented by physostigmine. 

Besides the intestine and stomach, a number of other muscular 
organs are thrown into contraction by physostigmine — ureter, bladder, 
uterus and bronchial muscle. The Intraocular Muscles also undergo 
contraction, and their movements under physostigmine have been the 
subject of a large number of investigations and of a good deal of con- 
troversy. The pupil contracts when physostigmine is employed either 
locally or internally, and this contraction may be lessened by the sub- 
sequent application of atropine, but is not altogether removed except 
by large quantities. On the other hand, the dilatation of the pupil 
produced by small quantities of atropine may be diminished by physos- 
tigmine, but the resulting contraction is much less than that caused 
by physostigmine applied to the normal eye. The ciliary muscle is 
acted on in the same way as the pupil^ so that the eye becomes accom- 
modated for near distance, and atropine induces the same modifica- 
tions. The effects of physostigmine, then, on the intestine, secretory 
organs, pupil and ciliary muscle are strictly analogous, and are gen- 
erally attributed to the alkaloid stimulating the terminations of the 
nerves in these organs. 1 It therefore resembles pilocarpine and mus- 
carine but its antagonism to atropine is much more complete, and a 
renewal of the secretion or contraction after atropine can be elicited 
much more easily by physostigmine than by muscarine or pilocarpine. 
The intraocular pressure is considerably reduced by the application of 
physostigmine to the eye and this has generally been attributed to the 
contraction of the pupil facilitating the escape of the fluid by allowing 
it freer access to the spaces of Fontana. But the latest writer on the 
subject, Gronholm, states that it is due to a contraction of the intra- 
ocular vessels, which lessens the secretion. 

Physostigmine is Excreted in the urine mainly, appearing in it a few 
minutes after its injection. It has also been found in the saliva and bile. 

The symptoms of poisoning with Calabar bean are identical with 
those caused by physostigmine, except when an old preparation con- 
taining calabarine is used, when some stimulation of the spinal cord 
may be induced. 

Preparations. 

Physostigma (U. S. P.), Physostigmatis Semina (B. P.), Calabar or Or- 
deal bean, the seeds of Physostigma venenosum. 

Extractum Physostigmatis (U. S. P., B. P.), 0.015-0.06 G. (i-1 gr.). 

1 Another theory formulated by Harnack is that, while atropine acts on the termina- 
tions of the nerves in these organs, physostigmine acts upon the organs themselves — 
on the secretory cells of the glands and on the muscle fibres of the intestine, pupil, etc. 



PHYSOSTIGMINE. 329 

Tinctura Physostigmatis (U. S. P.), 1-3 c.c. (15-45 mins.). 
Physostigmin^: Salicylas, eserine salicylate (U. S. P.), 0.003 G. (fa gr.). 
Physostigmine Sulphas, eserine sulphate (U. S. P., B. P.), 0.001-0.003 

G. (bWo gr-)- 

Lamellse Physostigminse, (B. P.), each containing Y -uos g r - of physostigmine 
sulphate. 

The sulphate and salicylate of physostigmine are colorless or faintly yel- 
low crystals, without odor, but possessing a bitter taste. The sulphate is 
deliquescent in the air and is very soluble in both alcohol and water. The 
salicylate is not deliquescent, has usually a slight acid reaction, and is solu- 
ble in 150 parts of cold, or 30 parts of boiling water. Both salts undergo 
decomposition when kept in solution and then assume a reddish-brown 
color ; the addition of boric or sulphurous acid to the solution is said to 
retard this decomposition. Preparations of the crude drug also lose their 
activity when kept for some time, but these are very seldom prescribed. 

Therapeutic Uses. — Physostigmine has been used for its depressant 
action on the central nervous system in cases of abnormal excitability 
of the cerebral cortex. In epilepsy and chorea it has received a fairly 
extensive trial, but has proved of little or no service in most cases, 
and is positively deleterious in some. The results in the treatment with 
it of other diseases of the central nervous system, such as tetanus, have 
been no more favorable, so that it has fallen into disuse. 

Its pharmacological action suggests no internal application of phy- 
sostigmine for which pilocarpine is not equally well fitted, and, as a 
matter of fact, physostigmine is now used only for its action on the 
intraocular muscles and tension. For this purpose a solution of J— 1 
per cent, is dropped in the eye, 2-4 drops at a time, or small discs of 
gelatin impregnated with the alkaloid may be applied to the conjunc- 
tiva (B. P.). The pupil begins to contract in 5-15 minutes, and at- 
taius its smallest size in half an hour. It remains contracted 12-14 
hours, and according to some observers a difference in the size of the 
two pupils may be made out for several days. The ciliary muscle 
contracts along with the iris, and the eye becomes accommodated 
for short distances. This action on the accommodation passes off in 
2-4 hours, but the sight is often rendered indistinct for some hours 
longer by alternate contraction and relaxation of the ciliary muscle. 
The action of physostigmine on the eye differs from that of muscarine 
for the former acts more on the pupil, the latter on the ciliary muscle, 
and the pupil is often contracted by physostigmine while the accom- 
modation is practically unchanged. The intraocular pressure is some- 
what increased at first and subsequently sinks. Its action in narrow- 
ing the pupil after atropine has been made use of to remove the dilation 
produced so frequently in ophthalmic surgery, but some newer tropeines, 
which produce a shorter mydriasis than atropine, have almost driven 
it from this field. It antagonizes the dilatation of the pupil after 
homatropine and cocaine much more successfully than that due to 
atropine. It has also been used in cases of synechia (attachment of 
the iris to the lens) alternately with atropine. The alternate contrac- 
tion and dilatation of the pupil would, it was hoped, break down the 
attachment, but the condition is now generally treated by operation. 



330 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

Physostigmine is now chiefly employed to reduce the intraocular 
pressure in glaucoma. 

Physostigmine Poisoning has occurred only from eating the bean as 
yet, and is to be treated by the usual methods of evacuation of the 
stomach and other general measures. It has been found by Fraser 
that atropine acts as an antidote to physostigmine in animals, and it 
might be tried in cases of poisoning. The full dose of atropine is 
required. 

Bibliography. 

Fraser. Edinburgh Medical Journal, ix., p. 36, 1864. Journal of Anat. and 
Physiol., 1867, p. 323. Practitioner, iv., p. 65. 

Bezold u. Gbtz. Centralbl. f. d. med. Wissenschaft, 1867, p. 241. 

Arnsteinu. Sustschinsky. Untersuch. a. d. physiol. Laborator. zu Wurzburg, ii., p. 81. 

Rogow. Ztschr. f. rationelle Heilkunde, xxix., p. 1. 

Heidenhain. Pfl tiger's Arch. f. Physiol., v., p. 309. 

Laschkewich. Virchow's Archiv, xxxv., p. 291. 

Harnack u. Witkowski. Arch. f. exp. Path. u. Pharm., v., p. 401. 

Harnack u. Meyer. Ibid., xii., p. 366. 

Turtschaninow. Ibid., xxxiv., p. 208. 

Schweder. Inaugural Dissertat., Dorpat, 1889. 

Hedbom. Skandinav. Arch, f . Physiol. , viii. , p. 209. 

Schultz. Arch. f. [Anat. u.] Phys., 1898, p. 66. 

Rothberger. Pfliiger's Arch., lxxxvii., p. 117. 

Grunholm. Arch. f. Ophthalmol., xlix., p. 620. 

Resume. — A number of the groups of alkaloids discussed up to this 
point act on the same peripheral organs and generally present some diffi- 
culty to the student, so that a few general remarks regarding them may 
be of service. These drugs acts at two distinct points — the peripheral 
ganglia and the terminations of the nerves in the muscular or glandu- 
lar tissues. Nicotine, curara and coniine affect the ganglia (Fig. 31, 
N) ; muscarine, pilocarpine, physostigmine and atropine the termina- 
tions in the organs (31, Fig. 31). Curara, coniine and atropine are 
purely depressant in their peripheral action ; nicotine is first stimulant 
and subsequently depressant, while muscarine, pilocarpine and physos- 
tigmine are practically purely stimulant. The action on the ganglia is 
quite independent of that on the nerve ends, and either may be stimu- 
lated or depressed after the others have been paralyzed. If, however, 
the nerve ends be paralyzed (Fig. 31, 2) as by atropine, changes in the 
ganglia will have no apparent effect, as the impulses arising from their 
stimulation are blocked in the nerve ends, and, on the other hand, their 
paralysis does not cause any further retardation of centrifugal im- 
pulses which are completely blocked already. After paralysis of the 
ganglia (Fig. 31, 3) the stimulation of the nerve ends is followed by 
the usual symptoms, because the impulses pass from the nerve ends to 
the epithelium directly without the intervention of the ganglia. Thus 
muscarine, pilocarpine and physostigmine act after the paralysis of the 
ganglia by nicotine or coniine. If the ganglia be paralyzed first, the 
paralysis of the nerve ends by atropine is followed by no change unless 
the latter have been in a state of activity. While it is universally 
acknowledged that atropine arrests the action of muscarine and pilo- 
carpine by paralyzing the points at which these unfold their action, 



RESUME. 



331 



Fig. 31. 



the subsequent stimulation of the paralyzed terminations by further 
administrations of muscarine or pilocarpine is by no means so generally 
believed. The statement that a paralyzed organ cannot be further 
stimulated seems to have assumed almost the authority of a theological 
dogma, although numerous points not only in the peripheral action of 
these drugs, but also in that of others on the central nervous system 
cannot be easily explained ex- 
cept on the opposite assumption. 
Some of the difficulties confront- 
ing the advocates of this theory 
have been already mentioned, 
and others will be met with in 
the course of this work. If it be 
granted that a paralyzed tissue 
may be restored by the action of 
stimulant drugs, the action of the 
foregoing alkaloids is much sim- 
plified. Thus atropine paralyzes 
the nerve terminations, but these 
may be restored to activity by 
very large quantities of muscarine 
or pilocarpine, unless the quan- 
tity of atropine given has been 
too large. The quantity of 
physostigmine required to re- 
store them is much smaller than 
that of pilocarpine, and its ap- 
plication is therefore much more 
successful in reinstating the con- 
dition of active stimulation. 
These differences between pilo- 
carpine and physostigmine may 
perhaps be explained on the 
analogy of the chemical theory 
of mass action ; the " affinity " 
of atropine for the nerve endings 
is then greater than that of any 
of the other alkaloids under dis- 
cussion, that of physostigmine 
next, and 



Jr-Tfk M 



A 




Diagram of a nerve fibre supplying a secretory 
gland. N, terminations of the cerebrospinal 
nerve round a ganglion cell. M the termina- 
tions in the epithelium of the sympathetic fibre 
from the ganglion cell. In 1 the connection be- 
tween the central nervous system and the secre- 
tory cells is intact, and secretion may be induced 
by impulses from the centres, by stimulation at 
N or at M. In 2 all connection between the 
nerve and the epithelium is broken off, and se- 
cretion can be induced only by stimulation of 
the secretory cells or by restoring the connec- 
tion. In 3 the connection is interrupted in the 
ganglion, and secretion can be caused only by 
drugs acting directly on the epithelium or on 
the terminations 31. 

and 

mentioned are therefore expelled from their combination with the 
protoplasm by very small quantities of atropine, and have to be given 
in very large quantities to remove the atropine from its combination. 
On the other hand, the attraction of physostigmine for the nerve ends 
seems much greater ; larger quantities of atropine are required to dis- 
place it, and smaller quantities of physostigmine restore the activity 
of the nerve ends. 



that of pilocarpine 
muscarine least. The last 



332 ORGANIC DRUGS ACTING AFTER ABSORPTION. 



XVII. ACONITINE. 

This series embraces a number of alkaloids, which resemble each 
other so closely in their chemical and pharmacological properties as to 
allow of their being treated together. Some of them which were 
formerly believed to be perfectly distinct, are now said to be identical, 
and it is not improbable that future investigation will still further 
reduce the numbers of the group. 

These alkaloids are found in a number of species of the Aconitum 
genus, the best known of which are Aconitum Napellus containing 
Aconitine (C 33 H 45 N0 12 or C 34 H 47 NO u ), Aconitum ferox, Pseudaconitine 
(C 36 H 49 N0 12 ), and Aconitum Japonicum, Japaconitine (C 34 H 49 NO n ). 

When aqueous solutions of these alkaloids are heated, they are 
broken up into one or more acids and simpler bases, so that they may 
be classed with those of the atropine and cocaine series, which are 
similarly decomposed. Aconitine forms acetic acid and Benzaconine 
(or picroaconitine), which may again be broken down into benzoic acid 
and Aeonine so that aconitine is acetyl-benzaconine. Pseudaconitine 
forms Pseudaconine, and Japaconitine Japaconine in the same way. 
These decomposition products are found in the plant and in the ordi- 
nary preparations, and in many of the commercial " aconitines " 
benzaconine and aeonine occur in varying proportions, so that their 
toxicity varies very considerably. 

Another alkaloid which resembles aconitine closely in its pharma- 
cological action, but which is less known, is Delphinine. It is found 
in stavesacre (Dephinium Staphisagria), along with a number of other 
bases, which may be the products of its decomposition. 

The symptoms caused by aconitine, pseudaconitine, japaconitine, and 
delphinine are very similar, differing mainly in degree and not in kind. 
Pseudaconitine is more poisonous than japaconitine which in turn is 
slightly more active than aconitine. Delphinine is much less poi- 
sonous. 

Symptoms. — After very large quantities of aconitine death may re- 
sult instantaneously, apparently from simultaneous failure of the heart 
and central nervous system. 

If smaller quantities be swallowed there is noted, after the ordinary 
bitter taste of the alkaloid, a feeling of warmth in the mouth and 
throat, which, agreeable at first, soon becomes prickling and tingling, 
and extends to the stomach and eventually to the skin. This is ac- 
companied by a profuse flow of saliva, and often by vomiting. The 
pulse is very slow, and may be irregular, and later becomes weak and 
imperceptible, when symptoms of collapse appear. The respiration 
is slow and labored, and great muscular weakness is complained of. 
After a time the smarting and tingling of the skin are no longer felt, 
and on examination the cutaneous sensibility is found to be much re- 
duced. The intelligence remains unimpaired to the last in many cases, 
although unconsciousness sometimes occurs, and death is generally, 



ACONITINE. 333 

but not invariably, preceded by convulsions. The pupil is unaffected 
except when convulsions supervene, when it is dilated. The prickling 
of the throat and skin is the most characteristic symptom, and is 
practically diagnostic in cases of poisoning, no other drug excepting 
veratrine having this effect. Death is due to paralysis of the respira- 
tory centre from the direct action of the poison, although this may be 
aided by anaemia of the medulla from the imperfect circulation. 

In small doses aconitine induces slowing of the heart and slight 
muscular weakness, which is often accompanied by tingling of the 
lips, tongue and throat. 

Action. — The prickling, tingling sensation is due to an affection of 
the Terminal Organs of the Sensory Nerves, as is shown by its appearing 
first at the point of application of the drug. Thus, when aconitine is 
swallowed the prickling and warmth is felt in the lips, tongue, and 
throat, and after small doses may be confined to these parts, while if 
an ointment containing aconitine be rubbed on the skin, the same sen- 
sation is induced locally. But no redness or swelling of the skin is 
induced, nor are blisters formed, so that aconitine differs entirely from 
the class of skin irritants (page 78). It evidently acts by stimulat- 
ing the terminations of the sensory nerves,. more especially those of 
common sensation, while the other sensory end organs have not been 
shown to be involved. Thus, apart from the bitter taste which it 
possesses in common with all alkaloids, aconitine has no effect upon the 
taste organs during this stage. The stimulation afterwards passes into 
depression, which induces a sense of numbness at the point of applica- 
tion, and in cases of poisoning, in all the surfaces of the body. The 
taste nerves seem to be involved in this effect, if Laborde's statement 
be correct that sweet substances have no taste after aconitine. The 
irritation of the sensory terminations often causes a number of reflexes, 
such as sneezing, coughing, increased secretion of saliva and vomiting, 
although some of these may be due in part to stimulation of the 
medullary centres. Evidence of the stimulation of Other Terminations 
is presented in fibrillary twitching of the muscles in the frog and 
sometimes in mammals. This is prevented by curara, but not by 
section of the nerves, and is therefore attributed to stimulation of the 
terminations of the motor nerves in muscles. The muscles themselves 
are comparatively little affected. Waller states that even minute 
quantities of aconitine abolish the irritability of nerve fibres when it 
is directly applied to them. 

The effects of aconitine on the Circulation are somewhat complex, as 
the heart is affected directly by it, as well as through its inhibitory 
nerves, and the vaso-motor centre is stimulated in addition. The 
frog's heart is first accelerated from the direct action of the poison, but 
this soon passes into the slow pulse and prolonged diastole which are 
characteristic of inhibitory action. The subsequent standstill mav at 
first be removed by atropine, but somewhat later this remedy fails, as 
the drug begins to act directly on the heart. A second acceleration 
may be thus induced, but the contractions soon become irregular, and 



334 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

groups of almost normal beats alternate with peristaltic movements 
which fail to expel any blood from the heart. Later, the large contrac- 
tions may alternate with periods of complete quiescence in the ventricle, 
while the auricles continue to beat, and stimulation of the accelerans 
nerve is followed by periods of regular contraction. The heart muscle 
seems to have lost in great part its power of conducting impulses, so 
that the contraction of the auricle often fails to excite a ventricular 
systole ; but if the conductivity be increased by stimulation of the 
accelerator nerve, or if the ventricle be excited by a series of electric 
shocks, it responds by rhythmical contractions. 

In mammals, the preliminary quickening of the heart is masked by 
the strong stimulation of the vagus centre. This produces marked 
slowing of the pulse, an increased dilation in diastole and a lessened 
systolic contraction ; the amount of blood leaving the heart is consider- 
ably reduced and the circulation is slackened. These symptoms are the 
only ones seen in the heart except with very large doses of the drug. 
They are shown to be due to the action on the inhibitory centres in 
the medulla by the fact that section of the vagus brings the heart back 
to its normal rate and extent of contraction. In medicinal doses, then, 
the only effect of aconitine on the heart is due to the vagus stimulation, 
the direct cardiac action not coming into play, and the administration 
of aconite in therapeutics is one of the best methods of eliciting pure 
and unmixed inhibition. 

In fatal doses, aconitine exerts a further action on the heart, how- 
ever, for the direct muscular action now comes into play and the 
heart suddenly accelerates from the slow vagus rhythm to one far above 
the normal. At the same time it becomes irregular, with a tendency 
towards the formation of groups of imperfect contractions and of con- 
tractions originating in the ventricles independently of the auricles. As 
the action becomes more intense, the irregularity increases, and eventu- 
ally the heart passes into delirium. A curious fact has been noted by 
several observers — that after section or paralysis of the vagus, a much 
larger quantity of aconitine is required to produce the acceleration and 
final delirium than when the nerves are intact. It has generally been 
stated that the cause of the acceleration is paralysis of the vagus termi- 
nations, but besides this there is evidently strong stimulation of the 
cardiac muscle, for the acceleration occurs after division of the vagi 
and even in the excised heart. The auriculo-ventricular rhythm is 
disturbed, the auricle often beating at a different rate from the ven- 
tricle, and the alternate consonance and dissonance of their contractions 
partly explains the variations in the ventricular rhythm and strength. 

The blood-pressure in mammals falls rapidly from the lessened out- 
put of the heart in the stage of vagus stimulation. There is some 
evidence of an action on some part of the vaso-motor mechanism as 
well, for some observers have noted a rise in arterial pressure after 
aconitine in animals in which the vagi had been divided or paralyzed 
before the exhibition of the drug. The fact that the vagus centre is so 
strongly stimulated would also suggest the probability of some increase 



ACOMTINE. 335 

in the activity of the vase-motor area. After the stage of acceleration 
has set in, the blood-pressure becomes extremely irregular, alternately 
sinking to zero and remaining at that point for some seconds and again 
attaining a fair height. These variations are evidently due to the 
alternations in the heart's movements. The vaso-motor centre seems 
eventually to become paralyzed, for it has been found that stimulation 
of an afferent nerve produced no change in the tension, while stimula- 
tion of the efferent vaso-motor nerves still caused a marked increase. 
The vaso-motor nerves and their terminations in the periphery seem to 
be unaffected by this poison. 

The Respiration is early affected by aconitine ; it becomes much 
slower, the movements are more labored than normally, and the ani- 
mal suffers from marked dyspnoea. The accessory respiratory muscles 
contract vigorously, and the movements of the abdominal expiratory 
muscles are so powerful as to suggest the movements of vomiting 
rather than of respiration. In fatal cases the respiration soon be- 
comes interrupted by convulsions, and in the intervals between these 
becomes weaker and eventually ceases. Various explanations of the 
respiratory phenomena have been given. It is certainly not due to 
action on the phrenic terminations, for the diaphragm contracts on 
electrical stimulation of these nerves after its spontaneous movements 
have ceased. The dyspnoea resembles somewhat that seen on stimu- 
lation of the centripetal fibres of the vagus, and the theory has been 
propounded that aconitine stimulates the vagus terminations in the 
lungs in the same way as the sensory terminations in the skin. The 
same dyspnoea is seen, however, when aconite is given after section of 
the vagi, so that it seems to be due to some action on the respiratory 
centre. 

The action of aconitine on the Central Nervous System is still a 
matter of dispute, as the effects on the peripheral nerve-ends tend to 
obscure the symptoms, but there can be no doubt that certain parts are 
stimulated. Thus, the vagus centre is undoubtedly thrown into a con- 
dition of increased irritability, for inhibition of the heart is a marked 
feature of the action . Probably the vaso-constrictor centre also under- 
goes some stimulation, and the vomiting so often seen may be caused, 
at least in part, by increased irritability of the medullary centres. 
The convulsions seen in both cold- and warm-blooded animals also 
point to central stimulation, and the respiratory symptoms are certainly 
of central origin, though their explanation is still unknown. The 
higher centres seem to be almost unaffected by the drug, for conscious- 
ness has often remained to the end, and when this is not the case, the 
mental symptoms are to be ascribed to the changes in the heart and 
respiration. The stimulation produced by aconitine is therefore con- 
fined to some of the lower divisions of the central nervous system — 
more particularly to the medulla oblongata. Some authors suppose 
that the paralyzing action which succeeds the stimulation, is more 
marked in the sensory than in the motor sphere and as evidence of this 
it has been pointed out that in frogs the reflexes disappear before the 



336 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

voluntary movements, but this is explained by the anaesthetic action of 
aconitine on the skin and cannot be accepted as evidence. The paralysis 
advances much more rapidly in the respiratory centre than elsewhere 
and death occurs from asphyxia, while the rest of the central nervous 
system is shown to be still irritable by the occurrence of convulsions. 

The muscular weakness often complained of after comparatively small 
quantities may be due to the depression of the circulation through the 
inhibitory action, or to nausea. 

The Secretion of saliva is greatly increased by aconitine from the 
irritation of the sensory terminations in the mouth and from the nausea. 
The cold perspiration observed in poisoning may be ascribed to the 
collapse rather than to any direct action on the sweat glands, although 
Aubert states that aconitine is a powerful diaphoretic in itself. 

Aconitine causes a marked fall of Temperature both in fever and in 
normal animals, but the precise way in which this action is elicited is 
unknown. Brunton and Cash found that after aconite the temperature 
fell more rapidly than usual if the animal was kept in a cool bath, but 
rose more readily if it was subjected to external warmth. The fall in 
temperature is generally ascribed to the depression of the circulation 
from the inhibitory action, but this observation would seem to indicate 
that aconite also acts upon the centres regulating the temperature of 
the body. 

In cases of Poisoning in animals atropine has been found to alleviate 
the symptoms and not infrequently to lead to recovery after doses which 
would otherwise have been fatal. This improvement is more espe- 
cially marked in the respiration which may resume its normal charac- 
ter and persist until heart paralysis sets in. Boehm explained this by 
a supposed action on the terminations of the vagus in the lung, but it 
is more probably to be ascribed to the stimulant action of atropine on 
the respiratory centre. In those cases the cause of death is said to be 
cardiac paralysis, but the stage of irregularity and the final delirium 
cordis is certainly retarded very considerably by atropine. Atropine 
appears to be the antidote from which most is to be hoped for in cases 
of aconite poisoning. 

Aconitine is Excreted mainly by the urine. Minute quantities have 
also been found in the saliva and bile. 

Benzaconine is very much less poisonous than aconitine and, in fact, can 
scarcely be included among active poisons, though very large quantities act 
on the heart, slowing it and rendering it irregular, and also depress the 
respiration. It has no effect on the sensory terminations. Aconine itself is 
almost inactive, but large quantities strengthen the heart beat and paralyze 
the terminations of the motor nerves like curara. It seems unlikely that 
these alkaloids have any influence on the action of the aconite preparations, 
although the possibility cannot be excluded at present. 

The alkaloids obtained from some other species of Aconitum have been 
found to differ considerably from aconitine and pseudaconitine in their ac- 
tion. In Aconitum septentrional e three bases lappaconitine, septentrionaline 
and cynoctonine have been discovered. Lappaconitine causes clonic convul- 
sions, vomiting, dyspnoea and finally paralysis of the respiration and heart, 



AGONITINE. 337 

and in the frog lessens the sensibility of the skin. Septentrionaline does not 
cause poisoning when taken internally, but injected subcutaneously induces 
local anaesthesia and later paralysis of the motor terminations like curara. 
Cynoctonine is also inactive when swallowed and is less poisonous than the 
others when applied by hypodermic injection when it causes tonic and 
clonic convulsions which are not generally followed by paralysis. Two 
alkaloids, lycaconitine and myoctonine, have been found in Aconitum lycocto- 
num, and induce almost identical symptoms. They increase the reflex 
excitability, and this is followed by convulsions and later by paralysis of the 
terminations of the motor nerves and by failure of the heart. 

Preparations. 

Aconitum (U. S. P.), Aconiti Radix (B. P.), the root of Aconitum Na- 
pellus, monk's-hood. 

Tincture Aconiti (U. S. P.), 1-5 drops every 1-3 hours. 

Tinctura Aconiti (B. P.), 5-15 mins. If frequently repeated, 2-5 mins. 

Extractum Aconiti (U. S. P.), 0.01-0.06 G. (|-1 gr.). 

Extractum Aconiti Fluidum (U. S. P.), 0.05-0.1 c.c. (1-2 mins.). 

Linimentum Aconiti (B. P.). 

Aconitina (B. P.), an alkaloid obtained from aconite root and having the 
formula C 33 H 45 N0 12 , It is almost insoluble in water but is freely soluble in 
alcohol. Commercial aconitine very often contains large amounts of aconine 
and benzaconine and therefore varies considerably in activity. 

Unguentum Aconitinse (B. P.), 2 percent. 

Staphisagria (U. S. P.), Staphisagriae Semina (B. P.), the dried ripe 
seeds of Delphinium staphisagria, stavesacre. 

Unguentum Staphisagrise (B. P.). 

Therapeutic Uses. — Aconite is employed to a considerable extent in 
England, the United States and France, while it has fallen into disuse 
in some other countries. Its pharmacological action suggests its use 
to slow and weaken the heart and circulation, to lower the temperature 
and to benumb the terminations of the sensory nerves in the skin. 
Digitalis is often prescribed to slow the pulse, but it has other effects 
on the heart and circulation, and where these are not indicated, aconite 
may well be used. Both drugs slow the pulse in the same way, but 
while aconite slackens the circulation and lowers the blood-pressure, 
digitalis accelerates the blood current and increases the arterial tension. 

The temperature is also reduced by aconite, but the newer antipy- 
retics have supplanted it for this purpose, as they are more certain and 
more powerful in their effects. The tincture is still prescribed how- 
ever, and ought to be given in small repeated doses. When fever 
is attended by a very quick pulse, aconite is especially likely to be of 
service, but it ought to be avoided when the heart is very weak. 

The action of aconitine on the sensory nerve terminations has been 
taken advantage of in cases of neuralgia, and there is decidedly much 
more reason for its use than for that of the great majority of drugs 
reputed to be beneficial in this condition. Either the tincture, or a 2 
per cent, solution of the alkaloid in oil, or the ointment of the B. P. 
may be employed externally. Aconitine has also been injected sub- 
cutaneously (y-g-p— iV m g-) i n neuralgia, but this mode of application 
is not to be recommended, as it causes very severe pain, which in some 
22 



338 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

cases lasts a long time. The internal administration of aconite in 
neuralgia does not seem to be followed by any improvement. Staves- 
acre is scarcely used in medicine at present. 

Bibliography. 

Liegeois et Hottot. Journ. dela Physiol., 1861, iv., p. 520. 

Plugge. Virchow's Arch., lxxxvii., p. 410. 

Ringer and MurrelL Journ. of Physiol., i., p. 232. 

Schellong. Inaug. Diss., Munchen, 1884. 

Giulini. Inaug. Diss., Erlangen, 1876. 

Boehmu. Wartmann. Verhandl. d. phys.-nied. Gesellsch. zuWiirzburg, 1872, p. 63. 

Ewers. Arch. f. exp. Path. u. Pharm., i., p. 385. 

Mennicke. Inaug. Diss., Halle, 1883. 

Anrep. Arch. f. [Anat. u.] Phys., 1880. Supplem., p. 161. 

Lubbe. Inaug. Diss., Dorpat, 1890. 

Dohrmann. Inaug. Diss., Dorpat, 1888. 

Rosendahl. Arb. a. d. pharmak. Instit. Dorpat, xi., p. 1 (very complete bibliography 
up to 1895). 

Matthews. Journal of Exp. Medicine, ii., p. 593. 

Cash and Dunstan. Transactions of the Koyal Society, cxc. , p. 239 ; ccviii., p. 39 and 
ccix., p. 97. 

XVIII. VERATRINE. 

Several species of the genus Veratrum have been found to contain 
alkaloids, the most important of which resemble each other in many 
respects, and also present many points of analogy to those of the 
preceding group. 

The chief members of this series are Veratrine (cevadine) and Proto- 
veratrine, the former of which is found in Veratrum Sabadilla (Asagrsea 
officinalis or Schoenocaulon officinale), cevadilla, and in Veratrum 
viride, Green Hellebore, 1 while the latter is the chief active principle 
of Veratrum album, White Hellebore. 1 

Each of these alkaloids is accompanied by a number of others, most of 
which are entirely inactive, while several of them are only weak poisons 
and possess little interest. In cevadilla, in addition to Veratrine, there are 
found Cevadilline, Sabadine, Sabadinine and another base, which is known 
as the Veratrine of Wright or Couerbe. In white hellebore Protoveratrine 
is accompanied by Jervine, Pseudojervine, Rubijervine, Protoveratridine and 
others. Green hellebore contains a little Veratrine along with Jervine, Pseu- 
dojervine and Rubijervine. Jervine, Sabadine and Sabadinine are known to 
possess some action on the organism ; cevadilline and Wright's veratrine have 
not been examined, while the others are said to be inactive. 

Veratrine (C 32 H 49 M) 9 ) and protoveratine (C 32 H 51 NO n ) are both 
powerful alkaloids, the latter almost rivaling aconitine in its toxicity. 
Veratrine can be decomposed into angelic acid and a base, cevine, 
which seems to be nearly related to aconine. Protoveratine is prob- 
ably a combination of isobutyric acid and a similar base. Veratrine 
occurs in two forms, one crystalline, the other amorphous ; the one 
passes easily into the other, and their effects are identical in animals. 

1 Hellebore is also the popular name of Helleborus niger, which differs entirely from 
Veratrum in its principles and also in its action. 



VERATRINE. 339 

The effects of veratrine on the central nervous system and the sen- 
sory terminations resemble those of aconitine very closely. On the 
other hand the muscles present a curious reaction to veratrine, which 
is entirely absent in aconitine poisoning. 

Symptoms. — The symptoms in man and other mammals commence 
with prickling and burning in the mouth followed by a sensa- 
tion of warmth in the stomach, marked salivation, nausea, and 
vomiting. The bowel is more involved in the effects, than is the case 
in aconitine poisoning, for violent purging accompanied by severe colic 
is a common symptom. The prickling sensation soon spreads from the 
mouth and throat to the skin, and is generally followed by profuse per- 
spiration. The pulse becomes slow and irregular, the respirations 
slow and labored. Fibrillary contractions of the muscles and convul- 
sions are generally observed, and after some time collapse sets in and 
is followed by unconsciousness and eventually by respiratory failure. 

Action. — When veratrine is applied in ointment to the Skin the same 
prickling, warm sensation may be elicited locally, and some of the 
poison is absorbed, as is shown by these symptoms sometimes occur- 
ring in other parts of the body. The cause of this is, as in the case of 
aconite, stimulation of the terminations of the sensory nerves. This 
action causes violent sneezing and coughing when small quantities of 
veratrine come in contact with the sensitive mucous membranes of the 
nose and throat and the Sabadilla is therefore known popularly in 
Germany as Nieswurz (Sneeze-wort). After the irritant action has 
lasted for some time, the sensory terminations in the skin become less 
sensitive, and a feeling of numbness and of cold is noted. Protovera- 
trine seems to cause less irritation of the sensory terminations than 
veratrine, and the subsequent local anaesthesia is more complete. 

The Terminations of the Motor Nerves are paralyzed in the frog by 
large quantities of veratrine, but this paralysis is not preceded by an 
increase in their irritability, as was formerly supposed. 

The Nausea and Vomiting which are invariably present in veratrine 
poisoning, may be due in part to the irritation of the sensory termina- 
tions of the stomach, but must probably be attributed for the chief 
part to central action. The salivation may be merely secondary to 
this emetic effect, or the poison may act on the salivary gland di- 
rectly. Nothing is known with certainty regarding the cause of the 
Purgation, but it is presumably induced by some action on the nervous 
mechanism of the intestine. The profuse Perspiration which follows 
the injection of large quantities of veratrine, and the cutaneous secre- 
tion noted in the frog, have been attributed to stimulation of the ter- 
minations of the nerves regulating the activity of the glands. 

The most characteristic action of veratrine, however, is that on the 
Striated Muscles. If a small quantity be injected into the lymph-sac 
of a frog a curious clumsiness and awkwardness in the movements 
becomes apparent, and after a few minutes it is evident that this is 
due to inability to relax its muscles. When a muscle is exposed, it is 
seen to contract as rapidly as usual, but instead of immediately relax- 



340 



ORGANIC DRUGS ACTING AFTER ABSORPTION. 



ing again, it remains shortened and offers resistance to the contraction 
of the opposing muscles. The animal can no longer coordinate its 
movements therefore ; for example, it can no longer extend a limb 



Fig. 32. 




Tracings of muscular contractions from the gastrocnemius of the frog, a, normal, b, three succes- 
sive contractions taken at intervals of one minute, five minutes after the injection of veratrine. The 
contraction is higher and much more prolonged than in a, and the lever returns very slowly to the 
hase line. 



immediately after flexing it, as it does ordinarily in crawling, and loco- 
motion becomes very slow and ungainly. 

This characteristic action is most easily seen on comparing the 
tracings obtained from a muscle stimulated directly by single induction 
shocks before and after the application of veratrine (Fig. 32). In the 
first part of the tracing it will be observed that the height of the con- 
traction is increased by veratrine, but this feature sinks into the back- 
ground before the marked prolongation of the second part of the curve. 
Instead of the almost instantaneous return to the base line seen in the 
normal tracing, the curve shows generally a slight undulation, and then 
a very slow fall, the period of relaxation generally being 20-30 times 
as long as that in the unpoisoned muscle, and the whole contraction 
lasting 5—10 seconds in favorable circumstances. If, however, the 
muscle be stimulated repeatedly at short intervals, so as to induce 
fatigue, the length of the curve decreases until it cannot be distin- 
guished from the ordinary muscle tracing ; a similar effect is produced 
by subjecting it to cold, or by heating it beyond a certain point, while 
moderate heat increases the abnormalities of the tracing. If an un- 
poisoned muscle be stimulated repeatedly, so as to induce fatigue, and 
veratrine be then injected, it is found that a marked improvement in 
the contraction occurs, so that while fatigue lessens the prolongation 
of the veratrine curve, veratrine removes to some extent the effect of 
fatigue. In the prolonged contraction more energy is used up than 
usual, and the amount of heat formed during muscular contraction is 
therefore increased by veratrine. Besides the alterations seen in the 
tracing, veratrine increases the irritability and absolute strength, so 



VERATRINE. 341 

that the muscle reacts to weaker stimuli and contracts against a greater 
weight than usual. 

The muscular phenomena are best observed in the frog, but can also 
be elicited in warm-blooded animals, although in the latter they do not 
play such an important role in the symptoms of poisoning. In the 
frog, the muscle is finally paralyzed, but this does not occur in mam- 
mals, as here the respiratory centre fails long before the quantity of 
veratrine necessary to induce this effect has been absorbed. 

The first explanation that suggests itself for the curious muscular 
phenomena, that they are due to some change in the nervous system, 
is negatived by the fact that excised muscles show exactly the same 
reaction. Bezold explained the prolongation by supposing that a 
change was produced in the muscle substance, by virtue of which a 
single stimulus was enabled to set up a tetanic contraction ; but this is 
shown to be incorrect, for if the nerve of another nerve-muscle prepa- 
ration be laid on the veratrinized muscle, no secondary tetanus is set up 
in it, as would be the case if the first muscle were undergoing tetanic 
contraction. The generally accepted view is that veratrine increases 
the catabolic changes in muscle, and thereby induces a prolongation of 
the period of active contraction, as well as an increase in the height of 
contraction and in the absolute strength. Fatigue, by reducing the 
amount of substance capable of undergoing catabolic change, and cold, 
by increasing its stability, counteract the effects of veratrine. 

In the tracing of veratrinized muscle a curious undulation is frequently- 
seen at the top of the contraction, or the ascent may at first be rapid, then 
slower, and then again more rapid. This has been ascribed to veratrine 
acting differently on the two forms of muscle fibre, the gray and the red, but 
this explanation has recently been shown to be erroneous (Carvallo and 
Weiss). Botazzi supposes that the initial contraction is due to the aniso- 
tropons substance, while the secondary slower and prolonged contraction is 
induced by increased activity of the sarcoplasm. The electrical organ of 
the torpedo is apparently affected by veratrine in the same way as striated 
muscle. 

Waller has recently shown that veratrine abolishes the irritability 
of the peripheral nerves when a solution is applied to them directly. 

Protoveratrine differs entirely from veratrine in its effects on the 
muscles and the terminations of the motor nerves. The latter are not 
paralyzed even by the largest quantities, while the contraction of the 
muscle is rather shortened than prolonged. The contraction is higher 
and the absolute strength is increased, but fatigue is induced more 
readily than in the unpoisoned muscle, so that protoveratrine appears 
to increase the muscular force temporarily, but leads to its early ex- 
haustion. 

Circulation. — The ventricular muscle of the frog's heart is affected 
by veratrine in very much the same way as the ordinary striated 
muscle, while the auricular muscle, consisting chiefly of unstriated 
fibres, is much less altered. The ventricular systole is at first stronger 
and more prolonged ; somewhat later one part of the ventricle is seen 



342 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

to remain contracted during the alternate diastoles of the rest, and 
waves of contraction spread over the heart resembling the peristaltic 
movements of the intestine rather than the ordinary contractions of 
the heart. The whole ventricle is smaller than usual, and but little 
blood is expelled into the aorta. Still later the persistent contraction 
spreads over the whole ventricle, so that it dilates only half as often 
as it did at first, while the auricles maintain their original rhythm. 
This is evidently due to action on the muscle ; the contraction is so 
prolonged as to limit the number of diastoles, and the ventricle can 
therefore react only to every alternate contraction of the auricle. 
After this " half-rhythm " has persisted for some time, the contractions 
become slower and weaker, and the heart finally comes to a standstill. 
The behavior of a frog's heart under veratrine resembles closely that 
characteristic of the digitalis series. 

In mammals, the chief circulatory symptoms arise from stimulation 
of the medullary centres resembling that seen in the earlier stages of 
aconite poisoning. The stimulation of the cardiac inhibitory centre 
produces slowing of the heart and a decrease in its output, while at the 
same time the peripheral vessels are contracted by the increased activity 
of the vaso-motor centre. After larger quantities the terminations of 
the vagus are paralyzed, and the vaso-motor centre is at the same time 
depressed, so that the pulse becomes quicker, but the blood-pressure is 
somewhat lowered. In the mammalian heart no such prolongation in 
the systole is seen as in the frog's, but that a slight stimulant action 
is exercised by veratrine is shown by the fact that very large doses 
quicken the rhythm even after atropine. Veratrine, therefore, seems 
to resemble aconitine in its effects on the mammalian circulation, but 
much larger quantities are required to produce the same effects, and 
the more evident symptoms of stimulation of the myocardium are not 
elicited. 

The Respiratory Changes under veratrine also resemble those under 
aconitine, and in both the cause of death is the same — paralysis of the 
respiration. 

The Central Nervous System seems to undergo stimulation under 
veratrine as under aconitine. This is evidenced by the convulsions 
seen in mammals as well as by the stimulation of the medullary centres 
already noted. After large quantities of the poison this stimulation 
gives place to paralysis, terminating in failure of the respiration. The 
highest centres seem less affected than the spinal cord and medulla 
oblongata, for complete consciousness has remained until immediately 
before death in several fatal cases. 

The Temperature is sometimes found lower than the normal after 
veratrine, probably owing to the slowing of the circulation. In other 
cases, when the convulsive movements are very marked and the heat 
production is therefore much increased, the temperature has been 
found somewhat higher than usual. In cases of poisoning in mammals 
atropine is said by Lissauer to have some value, probably owing to its 
action on the respiratory centre and on the vagus terminations in the heart. 



EMETINE. 343 

As regards the other alkaloids of this series, jervine, sabadilline and saba- 
dinine seem to possess the same action as veratrine, but are much less poison- 
ous. Protoveratrine, which as has been said, differs from veratrine chiefly 
in not prolonging the muscular contraction and in the effects on the sensory 
terminations, is much more poisonous. Its action resembles that of aconitine 
as much as that of veratrine, and it may therefore be regarded as a link con- 
necting the two groups. 

Pkepakattons. 

Veratrina (U. S. P., B. P.), a mixture of alkaloids obtained from the seeds 
of Asagrsea officinalis (U. S. P.); a mixture of alkaloids prepared from ceva- 
dilla, the dried, ripe seeds of Schcenocaulon officinale (B. P.), forms a white 
or gray, amorphous or semi-crystalline powder without odor, but causing in- 
tense irritation of the nostrils, with an acrid taste and leaving a sensation of 
tingling and numbness on the tongue. It is insoluble in water but soluble 
in alcohol. It contains veratrine and the other alkaloids of the plant. 

Unguentum Veratrinse (IT. S. P., B. P.). 

Oleatum Veratrinse (U. S. P.). 

Veratrum Viride (U. S. P.), American, or Green Hellebore, the rhizome 
and roots of Veratrum viride. 

Extractum Veratri Viridis Fluidum, 0.2-0.5 c.c. (3-6 mins.). 

Tinctura Veratri Viridis, 0.2-0.5 c.c. (3-6 mins.). 

Therapeutic Uses. — The therapeutic uses of the members of this 
series are extremely limited. Veratrine is used in the form of the 
oleate or ointment as an external application in cases of neuralgia, and 
is certainly a safer remedy than aconite. Neither its pharmacological 
action nor therapeutic experience supplies any indications for its inter- 
nal use. Veratrum viride is used internally in the same class of cases 
as aconite, but as its activity is due to veratrine it might well be dis- 
carded from the pharmacopoeia. Veratrum album is also a superfluous 
drug. 

BlBLIOGBAPHY. 

Bezold u. Hirt. Untersuch. aus dem phys. Laborat. zu "Wurzburg, i., p. 75. 

Kolliker. Virchow's Archiv, x., p. 257. 

Boehm. Studien tuber Herzgifte, 1871. 

Fick u. Boehm. Wiirzburger Verhandhmgen, iii., p. 198. 

Rossbach. Pniiger's Archiv, xiii., p. 607. 

Lissauer. Arch. f. exp. Path. u. Pharm., xxiii., p. 36. 

Brunton and Cash. Journ. of Physiol., iv., p. 1. 

Overend. Arch. f. exp. Path. u. Pharm., xxvi., p. 1. 

Eden. Arch. f. exp. Path. u. Pharm., xxix., p. 440. (Protoveratrine.) 

Schenk. Pfliiger's Archiv, lxi., p. 494. 

Hedbom. Skand. Arch. f. Phys., viii.,p. 197. 

Camallo et Weiss. Journ. de Phys. et Pathol., i., p. 1. 

Botazzi. Arch. f. [Anat. u.] Phys., 1901, p. 377. 

Garten. Pfliiger's Arch., lxxvii., p. 485. 

Buchanan. Journ. of Physiol., xxv., p. 137. 

XIX. EMETINE (IPECACUANHA). 

Ipecacuanha (Cephselis Ipecacuanha) has long been used for its 
emetic and expectorant virtues, and was until recently believed to 
contain only one alkaloid, Emetine. Paul and Cownley have shown, 
however, that this so-called principle is really made up of two distinct 
alkaloids, Cephceline (C 14 H 19 N0 2 ) and Emetine (C 11 H 18 (CH 3 )X0 2 ), both 



344 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

of which are quinoline derivatives and produce almost identical ef- 
fects. It seems probable that one or both of them are formed by a 
number of other plants, some of which have been used as emetics in 
former times, and among which may be mentioned several species of 
violet. Their chief action is exerted on the alimentary canal, although 
they are also local irritants. 

Symptoms and Action. — When administered internally emetine has 
a bitter, acrid taste, and produces a copious, salivary secretion, fol- 
lowed later by nausea and vomiting with the usual attendant symp- 
toms. The drug is generally largely eliminated by vomiting, so that 
no further effects are observed. When injected hypodermically, 
however, it induces nausea, vomiting and purging, and blood is fre- 
quently voided in the stools, a condition of collapse follows, and the 
animal generally dies of exhaustion in the course of a few # hours after 
the onset of the symptoms. Very large quantities injected subcuta- 
neously or intravenously may fail to elicit vomiting, but the collapse 
symptoms appear, and after some weak convulsive movements, the 
animal dies of cardiac failure. In those cases in which death follows 
rapidly on the injection, no pathological lesions may be found after 
death, but in experiments where smaller quantities are injected, and 
the animal survives for 18-24 hours, the stomach and intestine often ex- 
hibit the appearances of an acute gastro-enteritis. The mucous mem- 
brane is swollen, congested and often covered with a muco-purulent 
secretion or studded with ecchymoses, and in dogs ulceration is often 
present. A lesion which is not by any means constant, but which 
occurs in a considerable number of animals and especially in rabbits, 
is oedema of the lungs. 

Emetine possesses a powerful Irritant Local Action, which is, how- 
ever, much more marked in certain individuals than in others. The 
smallest quantity of the powdered root of ipecacuanha is sufficient 
to induce in the subjects of this idiosyncrasy considerable swelling 
and injection of the conjunctival and nasal mucous membranes, with 
salivation, tears, sneezing, coughing and bronchial catarrh. When 
applied to the skin as a liniment, it produces redness, itching and oc- 
casionally a pustular eruption, and injected subcutaneously it causes 
pain and inflammation, often terminating in abscess. Its action on 
the alimentary canal also indicates its irritant properties. It has been 
much discussed whether the emesis is wholly due to this irritant action 
on the gastric mucous membrane, or whether emetine, like apomor- 
phine, has a specific action on the centres in the medulla oblongata con- 
trolling vomiting. In view of the fact that emetine, like many other 
irritants when injected subcutaneously, has a specific action on the ali- 
mentary canal it seems unnecessary to have recourse to any action on 
the central nervous system, and almost all the facts brought forward 
as evidence of this supposed central action have been disproved. 

It is sometimes stated that section of the vagus nerves does not prevent 
ipecacuanha from causing vomiting, whereas if it only irritated the stomach, 
the division of these nerves (which are probably the chief sensory nerves of 



EMETINE. 345 

the stomach) ought to prevent it by hindering the impulses reaching the 
medulla and setting up reflex processes there. But this statement has been 
contradicted, and no great weight can be laid on the argument in any case, 
because section of the vagus alone causes violent and persistent vomiting very 
often. Thumas states that the application of emetine solutions to the 
medulla provokes vomiting, but this method is so open to objection that his 
inference that the alkaloid acts on the vomiting centre, can hardly be re- 
garded as justifiable. On the other hand, it may be urged that if emetine 
acted on the medullary centre, vomiting ought to follow after smaller doses 
and more quickly when it is injected subcutaneously, being thus more rapidly 
absorbed, than when it is taken up from the stomach. But this is not the 
case, for ipecacuanha causes emesis as soon and in as small quantities when 
it is administered by the stomach, whereas apomorphine which acts on the 
centre directly, acts much more rapidly and efficiently when it is injected 
subcutaneously. While the question cannot be said to be definitely settled, 
almost all the facts point to peripheral gastric, and not to central action. 

Emetine injected into a vein weakens the heart's action, and induces a fall 
of blood-pressure, but when it is injected subcutaneously or given by the 
mouth the heart is much less affected. 

In the frog, emetine does not cause vomiting, but a slowly advancing central 
paralysis follows its injection, the spontaneous movements ceasing early, 
and later the reflex excitability disappearing. The contractions of the heart 
are rendered weak and irregular, and eventually cease from paralysis of the 
cardiac muscle. 

The striated muscle of the frog has been said to be weakened and 
paralyzed by emetine, but this has been disputed, and the muscular action 
is in any case slight and unimportant in frogs poisoned with the alkaloid. 

The nausea and vomiting are accompanied by the usual symptoms — 
muscular weakness and depression, increased secretion of saliva and of 
mucus by the glands of the throat and respiratory passages, often per- 
spiration and generally temporary acceleration of the pulse. (See 
apomorphine, p. 235.) Most of the researches on which the above 
statements are based have been performed with "emetine," which, 
according to Paul and Cownley, contains pure emetine and cephseline. 
The two constituents seem to resemble each other very closely in their 
effects, however, cephseline being somewhat more powerful than pure 
emetine. 

Emetine and cephseline have not been used in practical therapeutics, 
various preparations of the crude drug being prescribed instead. Their 
isolation is so difficult that it seems unlikely that the pure alkaloids 
will be made use of in the near future, and from a comparison of their 
effects with that of ipecacuanha it scarcely seems desirable that they 
should be introduced. For ipecacuanha is much less liable to produce 
purging than emetine, probably because the solution of the alkaloids 
is retarded by the presence of large quantities of tannic acid and other 
impurities, while at the same time the emetic action is but little slower 
than that of emetine. Neither emetine nor ipecacuanha preparations 
are suitable for hypodermic injection owing to their irritant properties. 

Preparations. 

TJ. S. P. — Ipecacuanha, the root of Cephaelis Ipecacuanha. The powdered 
root is prescribed in dysentery in quantities of 2 G. (30grs.); emetic, !2 G. 
(30 grs.); expectorant, 0.06-0.3 G. (1-5 grs.). 



346 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

Extractum Ipecacuanha? Fluidum, expectorant, 0.2-0.5 c.c. (3-8 mins.); 
emetic, 2 c.c. (30 mins.). 

Syrupus Ipecacuanha, | expectorant, 0.1-1 c.c. (2-15 mins.); emetic, 

Vinum Ipecacuanha, j 2-4 c.c. (£-1 fl. dr.); for a child. 

Trochisci Ipecacuanhas. 

Trochisci Morphina et Ipecacuanha ; each contains 0.0016 G. (?Vgr.) 
of morphine sulphate. 

Tinctura Ipecacuanha et Opii contains 10 per cent, opium, i. e. } is of 
the same strength as laudanum, 0.3-1 c.c. (5-15 mins.). 

Pulvis Ipecacuanha et Opii (10 per cent, opium), Dover's Powder, 
0.3-1 G. (5-15 grs.). 

B. P. — Ipecacuanhae Radix, the dried root of Psychotria Ipecacuanha, 
expectorant, £-2 grs. ; emetic, 15-30 grs. 

Extractum Ipecacuanhas Liquidum, expectorant, £-2 mins.; emetic, 15-20 
mins. 

Acetum Ipecacuanhas, 10-30 mins. 

Yinum Ipecacuanha, expectorant, 10-30 mins. ; emetic, 4-6 fl. drs. 

Trochiscus Ipecacuanhas, contains £ gr. of the powdered root. 

Trochiscus Morphina et Ipecacuanha, each contains & gr. of mor- 
phine hydrochloride. 

Pulvis Ipecacuanha Compositus, Dover's Powder, 10 per cent, opium, 
5-15 grs. 

Pilula Ipecacuanhas cum Scilla, 4-8 grs. This pill is formed from Dover's 
Powder, and contains about 5 per cent, of opium. 

Therapeutic Uses. — Ipecacuanha has been largely employed as an 
emetic, and although it has been replaced for some purposes, notably 
in cases of poisoning, by apomorphine, it still has a certain field of use- 
fulness in cases in which an emetic is indicated but in which the hypo- 
dermic method is objectionable, as in children . At present, ipecacuanha 
is used chiefly as an expectorant in the treatment of inflammatory 
conditions of the respiratory passages. For this purpose it is prescribed 
in very much less quantities than those necessary to produce emesis. 
It acts indirectly through its nauseating properties, and has the ad- 
vantage that its action is much more prolonged than that of apomor- 
phine, and at the same time is not so depressant as that of several 
metallic substances, such as tartar emetic, which are used for the 
same purpose. It increases the secretion of the bronchial mucous mem- 
brane, and further tends to render it more fluid, so that the mucus can be 
coughed up more easily. The increased secretion may also be of 
service by protecting the inflamed and irritable membrane from the cold 
air and thereby lessening the cough, and in order to strengthen this ac- 
tion ipecacuanha may be prescribed in combination with opium, either 
as a lozenge or in the famous Dover's powder. When the secretion of 
the bronchi is already excessive, and the cough is rather to be encour- 
aged than repressed, these preparations are of course con train dicated. 

Ipecacuanha is also employed as a diaphoretic, either alone or more 
commonly as Dover's powder. The perspiration is not so copious as 
that following pilocarpine and other diaphoretics, but resembles rather 
that produced by warmth applied to the skin. Dover's powder is 
therefore a common remedy in chills and in commencing catarrh of the 
respiratory passages. 



COLCHICINE. 347 

Ipecacuanha is used very largely in dysentery, particularly in tropical 
dysentery, in which it seems to act almost as a specific. Its effect is 
attributed by some authorities to the large amount of tannic acid con- 
tained in the root, and a preparation of ipecacuanha from which the 
alkaloids have been removed (Ipecacuanha Deemetinisata) is said to be 
as valuable in these cases as the unaltered drug. Others are inclined 
to ascribe some of the virtues of ipecacuanha to the alkaloids, and deny 
that the same results are obtained by the use of this preparation. The 
purified powder has the advantage of not causing any nausea or vomit- 
ing, and is certainly to be preferred to the crude root if the claims of 
its advocates prove to be well founded. Very large quantities of the 
powdered root are generally required in dysentery. Many prescribe 
enough to cause vomiting at first, and then follow this up with smaller 
quantities which are used along with morphine or ice, or with sina- 
pisms to lessen the nausea and vomiting. Others give a few drops 
of laudanum at once, and when the medullary irritability is thus 
reduced, and there is less danger of vomiting, prescribe 30-60 grs. 
(2-4 G.) of the powdered root, and continue the treatment with 
smaller doses. 

Ipecacuanha has been recommended in very small quantities as 
a stomachic, even in cases of vomiting, and its action on the mu- 
cous membrane might be expected to be of value in some cases ; but 
it very often fails to have any effect, and is not widely used for this 
purpose. 

Bibliography. 

Dyce Duckworth. St. Bartholomew Hospital Reports, v., p. 218 ; vii., p. 91. 
Podwyssotzki. Arch. f. exp. Path. u. Pharm., xi., p. 231. 
Thumas. Virchow's Arch., cxxiii., p. 66. 
Wild. Lancet, 1895, ii., p. 1274. 

XX. COLCHICINE. 

Colchicine and colchiceine are two nearly related bodies found in the 
seeds and corm of Colchicum autumnale, which owes its activity to 
their presence. They are generally included among the alkaloids, but 
differ from the other members of this class in possessing an acid reac- 
tion. Their chemical structure is still imperfectly known, but they 
do not seem to contain a pyridine ring ; colchicine [C 15 H 9 (OCH 3 ) 3 - 
(NHCOGH 3 )COOCH 3 ] is the methyl ether of colchiceine [C 15 H 9 - 
(OCH 3 ) 3 (NHCOCH 3 )COOH] . These two principles are apparently 
identical in their effects, which are observed chiefly in the alimentary 
canal. 

Symptoms. — No symptoms whatever follow the use of colchicum in 
ordinary therapeutic quantities. After the administration of a poison- 
ous dose to man or animals several hours elapse before any symptoms 
are elicited, and the amount injected has but little influence on the 
duration of this preliminary stage. Whether given by mouth or hypo- 
dermically, colchicine produces symptoms of discomfort in the stomach 



348 ORGANIC DRUGS ACTING AFTER ABSORPTION 

and intestine. Pain in the gastric region is followed by salivation, 
nausea, vomiting, and diarrhoea. At first the evacuations are the 
ordinary contents of the stomach and intestine, but afterwards a quan- 
tity of sticky mucous fluid may be ejected, often streaked with blood. 
Later, a condition of depression, apathy and collapse follows, and the 
movements become slow and difficult, more especially in the posterior 
extremities, which eventually become completely motionless ; the 
paralysis then progresses upwards until the movements of the fore 
limbs and respiratory muscles are involved, when death occurs from 
asphyxia. In man, the intelligence remains until death, though there 
is generally some giddiness and precordial anxiety, and occasionally 
some confusion or even delirium preceding the collapse. 

In mammals poisoned with colchicine, the alimentary canal exhibits 
all the appearances of acute gastro-enteritis, with numerous ecchymoses 
especially in the upper part of the bowel. In less acute cases these 
inflammatory symptoms are less marked, and in man there is seldom 
more than catarrh of the duodenum. 

The Circulation is but little affected apparently. In animals the 
blood-pressure and heart rhythm remain normal, and though a small, 
rapid pulse may be one of the features of the poisoning in man, this 
is due to the collapse rather than to any direct action on the circula- 
tory organs. 

The Respiration is slow, but is deep and full at first. Later it be- 
comes shallow, and the failure of the centre is the cause of death, the 
heart continuing to beat for some time afterwards. 

The Movements of the Bowel are much hastened when the symptoms 
set in, and Jacobj believes that this is due to an increase in the irrita- 
bility of the nervous mechanism, which accordingly reacts more strongly 
than usual to the natural stimuli ; but this is entirely inadequate to 
explain the acute inflammatory appearances, which are evidently due 
to an irritant action on the mucous membrane. 

When Locally Applied to sensitive mucous membranes, or when in- 
jected hypodermically, colchicine is intensely irritating, producing 
redness and prickling in the skin, and a burning sensation in the 
mouth and throat. 

The Nervous Symptoms are supposed by some to be due to a direct 
action on the central nervous system, but may probably be ascribed 
rather to a condition of collapse produced indirectly through the action 
on the abdominal organs. It is true that in many cases, especially in 
man, the post-mortem appearances do not indicate any marked alter- 
ation of the stomach and intestine, but the symptoms throughout in- 
dicate that the nervous effects are indirect in their origin, and not due 
to any direct depression of the brain cells. When the collapse symp- 
toms appear, a certain degree of insensibility to external impulses may 
be made out in the integument, but this seems due rather to the gen- 
eral depression than to any real anaesthesia of the skin. 

The influence of colchicine on the Kidneys varies, for in some cases 
complete anuria is produced for many hours, while in others the urine 



COLCHICINE. 349 

is slightly increased. The constituents of the urine are not materially 
altered by ordinary therapeutic doses of colchicum, and, in particular, 
the uric acid shows no constant change in amount. In animals bloody 
urine is sometimes passed after colchicine. 

All of those symptoms are exactly those caused by a large number 
of poisons, including some of the bacterial toxines and the heavy 
metals. Many local irritants when injected into the blood or when 
absorbed from the subcutaneous tissue or the alimentary canal, exercise 
an immediate, local action, which betrays itself in pain, or ecchymosis 
and swelling at the point of injection, but these symptoms pass oif in 
a short time and the animal becomes apparently normal for many 
hours or even days. At the end of this time, however, symptoms be- 
gin to develop at two points — in the alimentary canal and in the 
kidneys. The reason probably is that the poisons are excreted at 
these points and are either freed from some harmless combination in 
which they have circulated in the tissues, or perhaps collect in larger 
quantities in the excretory organs. At any rate, irritation and later 
acute inflammation are set up at these points. At first the irritation 
excites only diarrhoea and diuresis, but as it goes on gastro-enteritis 
and anuria or hematuria may be produced. The symptoms from the 
intestine and kidney may not be equally well marked ; at one time 
the one becomes inflamed while the other is only subjected to mild 
stimulation, while at other times both are the seat of acute inflamma- 
tion. The inflammation of the bowel produces a condition of collapse, 
which is seen also in various intestinal diseases, such as cholera. 
Sometimes the poisons (and also cholera) produce no very marked 
symptoms of gastro-intestinal disorder, but rather those of collapse, 
but there is no reason to believe that the collapse is due to any direct 
action on the central nervous system. 

In the frog, colchicine has little or no effect, but if the solution be exposed 
for some time to the air, it causes a prolongation of the muscular contraction 
similar to that seen after veratrine, and eventually a tetanus resembling that 
due to strychnine. Jacobj therefore believes that in mammals the effects 
are not produced by colchicine itself, but by a substance formed by its oxida- 
tion in the tissues, oxydicolchicine. The frog's tissues are unable to oxidize 
colchicine, but if oxydicolchicine be formed by the exposure of colchicine 
to the air, it produces these symptoms. Oxydicolchicine causes the same 
symptoms in mammals as colchicine. 

Preparations. 

Colchici Radix (U. S. P.), Colchici Cormus (B. P.), the conn or bulb of 
Colchicum autumnale, 0.1-0.3 G. (2-5 grs.). 

Extractum Colchici Radicis (U. S. P.), 0.03-0.1 G. (£-2 grs.). 

Extractum Colchici (B. P.), \-l gr. 

Extractum Colchici Radicis Fluidum (U. S. P.), 1-0.2 c.c. (2-3 mins.). 

Vinum Colchici Eadicis (U. S. P.), 0.5-1 c.c. (8-15 mins.). 

Vinum Colchici (B. P.) (10-30 mins.). 

Colchici Semen (U. S. P.), Colchici Semina (B. P.), the seed of Colchi- 
cum autumnale. 

Extractum Colchici Seminis Fluidum (U. S. P.), 0.1-0.3 c.c. (2-5 mins.). 



350 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

Tinctura Colchici Seminis (IT. S. P.), 0.3-1 c.c. (5-15 mins.). 
Tinctura Colchici Seminum (B. P.), 0.3-1 c.c. (5-15 mins.). 
Vinum Colchici Seminis (U. S. P.), 2-5 c.c. 
The Vinum Colchici Radicis is the preparation usually prescribed. 

Therapeutic Uses. — Colchicum has long been used in gout on purely 
empirical grounds. In fact, the pathology of gout is so obscure that 
no rational treatment for it can be looked for at the present day, and 
the efficacy of colchicum in this disease can, therefore, be argued solely 
from clinical experience, which here gives only uncertain indications. 
Up to a few years ago the routine treatment was wine of colchicum, 
but of late many physicians have denied that any benefit whatso- 
ever was obtained from its use. Others maintain that colchicum is 
at any rate the most efficacious drug available in many cases, and here 
the matter stands, but the use of colchicum in gout is not universal 
now, as it was formerly. Some attempt has been made to place the 
practice on a rational basis by showing that it increased the excretion 
of uric acid. But a number of other intestinal irritants have the same 
effect, and it now seems to be proved that gout is not due to a deficient 
excretion of uric acid, so that its increased elimination would not ex- 
plain the alleged beneficial effects of colchicum. Besides this increase 
in the uric acid excretion is by no means a constant result of colchicum 
medication, for it not infrequently has the opposite effect. And in 
gout the uric acid excretion does not seem to be modified at all by col- 
chicum. 

Colchicum has also been used in chronic rheumatism but here it is 
of little or no benefit. 

Bibliography. 

Jacobj. Arch. f. exp. Path. u. Pharm., xxvii., p. 119. 

N Paton. Brit. Med. Journ., 1886, i., p. 377, and Journ. of Anat. u. Phys. , xx., 
p. 267. 

Fawcett. Guy's Hospital Keports, lii., p. 115. 



XXI. SAPONIN, SAPOTOXIN AND SOLANINE. 

Under this group are arranged a number of glucosides which have 
many features in common both in their chemical properties and in their 
pharmacological action. Many of them have not yet been completely 
isolated, and it seems not unlikely that several which are now believed 
to be distinct, will prove to be identical. Kobert has found that many 
of them may be arranged in a chemical series C n H 2n _ 8 O 10 . Some have 
an acid reaction and form salts with the alkalies, while all possess the 
characteristic glucosidal reaction, being decomposed by acids and fer- 
ments into sugars and unknown inactive substances. The most poi- 
sonous among them are designated by the general term of Sapotoxins, 
while Saponin may be used to include the less active ones and certain 
innocuous isomers of the sapotoxins which are formed from them by 
boiling with alkalies. These terms as well as the popular names of 
several of the plants from which the active principles are derived, 



SAPONIN, SAP0T0X1N AND SOLANINE. 351 

refer to the property they possess of forming frothy, soap-like solutions 
in water and of holding insoluble bodies in suspension in it. Very 
often several of these bodies are found in a single plant, either several 
powerfully poisonous ones (sapotoxins), a mixture of sapotoxins and 
saponins, or saponins only. 

Saponins or sapotoxins are found in about 150 species of plants. 
The chief of these are : 

Quillaja saponaria, or soapbark (containing quillaja-sapotoxin and 
quillajac acid). 

Saponaria officinalis, or soapwort (saporubrin and saponin). 

Cyclamen Europeum, or sowbread (cyclamin). 

Polygala senega (senegin and poly g alio acid). 

Agrostemma githago, or corncockle (agrostemma-sapotoxin). 

Gypsophila struthium and other species (gypsophila-sapotoxin). 

Chamselirium luteum, or blazing star (chamartirium-sapotoxiri). 

Smilax, various species, including those known as sarsaparilla (sarsa- 
ponin, sarsaparilla-saponin and parillin or smilacin). 

In addition to these plants, which owe their action to the presence 
of these bodies, a number of drugs contain saponins along with other 
more important principles. Thus, an almost inactive saponin (digi- 
toniri) is met with in digitalis, and similar saponins probably occur in 
several others of the digitalis series although they have not yet been 
isolated. 

The most poisonous of these are the sapotoxins of quillaja, agros- 
temma and gypsophila, quillajac acid, and cyclamin. Senegin is only 
about one tenth as poisonous as quillaja-sapotoxin, and the saponins 
prepared from the sapotoxins are still less dangerous. 

Another body closely resembling the saponin in action is Solanine, 
a glucosidal alkaloid found in many species of Solanum, such as S. 
nigrum (black nightshade), S. dulcamara (bittersweet), S. tuberosum 
(potato), and probably in some species of Scopolia. In Solanum nigrum 
and S. dulcamara it is accompanied by small quantities of one or more 
bases resembling atropine, while in dulcamara a glucosidal body, Dul- 
camarin, has been found also belonging to the sapotoxin series. 
Solanine is said to be generally accompanied by Solaneine, a nearly 
related alkaloid. Solanine breaks up on being heated with acids into 
sugar and a base, Solanidine, which retains the poisonous action. In 
some plants both solanine and solanidine seem to be present. 

Its chief importance arises from its occurrence in the potato, which 
has given rise to widespread poisoning in several instances. The 
amount of solanine in the potato is in general too small to provoke 
poisonous symptoms, even when enormous quantities are eaten, but 
when the potatoes begin to sprout in damp cellars, the percentage of 
solanine rapidly increases, especially in the green buds and the small 
young tubers. In old, rotting potatoes it may also become dangerously 
high, but cases of poisoning are more likely to arise from the use of 
the green, unripe potatoes than from those which are obviously unfit 
for use. Weil states that the increase in solanine seen in potatoes that 



352 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

have been kept too long is due to the presence of bacteria which form 
this alkaloid from the potato. 

In any case the potato skins contain nearly half of the solanine, 
and if these be removed before boiling, a considerable part of the 
alkaloid contained in the edible part is extracted by the water. 

Action. — The sapotoxins possess a very irritant, local action, and 
produce acute inflammation of the alimentary canal and extravasa- 
tions in various organs, when they are carried to them by the blood. 
They also destroy the red blood cells when brought into contact with 
them. 

They have a harsh, acrid, unpleasant taste, and when swallowed pro- 
voke nausea and often vomiting, with pain and colic, and less frequently 
diarrhoea. They are not absorbed by the normal epithelium of the 
alimentary canal, and therefore fail to produce general symptoms, un- 
less some lesion, such as gastric ulcer, is present. Thus pigs feed 
with avidity on Cyclamen and are unharmed by it unless some lesion 
of the intestine is present. The unbroken skin is not affected by a 
single application as a general rule, and absorption is extremely slow 
from the subcutaneous tissues, in which they act as irritants, however, 
and produce inflammation and suppuration. The sapotoxin derived 
from Agrostemma differs from the others in being absorbed fairly 
rapidly from the alimentary canal and from the subcutaneous tissues, 
so that more dangerous symptoms may arise from it than from the 
other members of the series. 

In an epidemic of solanine poisoning from potatoes described by 
Schmiedeberg, the symptoms consisted of headache, colic, vomiting 
and diarrhoea, general depression and weakness, and some mental con- 
fusion. In severe cases pallor or cyanosis, dilated pupils, short periods 
of unconsciousness with acceleration and then slowing of the pulse 
were observed. All the patients recovered in the course of ten days. 
In many cases some rise of temperature was noted. In experiments 
on animals, Perles found almost the same symptoms and the same 
post-mortem appearances as after sapotoxin. Diarrhoea was not so 
easily induced by solanine as by the poisonous potato, perhaps because 
the pure poison was absorbed from the stomach, while it was carried 
into the bowel when mixed with the other constituents of the potato. 
Solanine, on the other hand, seems more liable to cause nephritis than 
most sapotoxins, and albumin and haemoglobin are generally found in 
the urine. When solanine is administered by the mouth, most of it is 
decomposed in the tissues, for very little reappears in the stools and 
urine as solanine and solanidine. 

When these bodies are injected directly into the blood vessels, they 
induce much more characteristic changes, which very often prove fatal 
after a longer or shorter interval. Very large quantities thus injected 
may kill animals within a few minutes from respiratory paralysis, and 
no characteristic appearances are to be found post mortem. Smaller 
doses induce depression, loss of appetite, sometimes vomiting and diar- 
rhoea, general weakness and collapse, with some dyspnoea and irregular, 



SAPONIN, SAPOTOXIN AND SOLANINE. 353 

feeble pulse. Weak convulsions appear just before the failure of the 
respiration, while the heart continues to contract for some minutes 
longer. In these cases ecchymoses are found in the serous membranes, 
pericardium, pleura and peritoneum, and occasionally in the kidneys. 
Endocarditis has been observed in some instances, but the most impor- 
tant alterations occur in the stomach and intestines, the mucous mem- 
brane of which is swollen and congested and contains numerous blood 
extravasations. The lymphatic glands of the abdominal cavity are 
also swollen and congested and often filled with haemorrhages. Oc- 
casionally the kidneys are found to contain numerous blood casts fill- 
ing the lumen of the tubules, and in these cases albumin and haemo- 
globin appear in the urine before death. In Cyclamen poisoning 
(from intravenous injection) hemoglobinuria is one of the earliest 
symptoms. 

The saponin bodies are general protoplasmic poisons, destroying life 
wherever they come in contact with living tissues in sufficient concentra- 
tion. Their irritant action on the mouth, throat, and stomach is the 
cause of the nausea and vomiting observed when they are administered 
in this way, and they cause sneezing and coughing from the same action 
in the nose and throat. On other mucous membranes, such as the con- 
junctiva, and in wounds, they cause similar irritation and inflamma- 
tion, which may be followed by suppuration. A form of local anaes- 
thesia often follows this irritation, the terminations of the sensory 
nerves apparently being benumbed, but the preliminary irritation pre- 
cludes their use for this purpose. 

Even the unbroken skin may be irritated when they are applied re- 
peatedly or rubbed on in the form of ointment. This irritation is be- 
trayed by redness, heat, itching, and eventually by the formation of 
pustules. Their local effects when injected subcutaneously also indi- 
cate their irritant properties. 

When the individual organs are exposed to the action of saponin 
bodies by the direct application of solutions to them, a similar poison- 
ous action is elicited. Muscle contracts more weakly even in dilute 
solutions, is eventually entirely paralyzed, and is altered in structure, 
the transverse striae of voluntary muscle and of the heart becoming 
very indistinct. Nerves exposed to solutions are also paralyzed in the 
same way, and the movements of cilia cease at once when they are ex- 
posed to sapotoxin bodies. The blood undergoes characteristic changes 
when it is acted on by saponin either in the vessels or in the test-tube. 
The coagulation is said to be accelerated by small quantities of cycla- 
min, and is certainly retarded by larger, but the most striking effect is 
the destruction of the red corpuscles and the liberation of the haem- 
oglobin, which forms " laky " blood. Even one part of cyclamin 
added to 100,000 parts of diluted blood completely destroys the red 
blood cells, while haemoglobin appears in the serum when consider- 
ably less poison is added. The other saponin bodies act less power- 
fully in this direction than cyclamin, but still produce distinct solution 
of the substance of the red corpuscles. When a saponin is injected 
23 



354 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

into the blood of a living animal this destruction of the red blood 
cells takes place to some extent, and the plasma contains haemoglobin, 
while the blood corpuscles are considerably diminished in number. 
This haemolytic action of the bodies of the group occurs after the cor- 
puscles have been hardened and killed by histological fixatives (Stew- 
art) and is therefore not dependent on the life of the blood cells ; it has 
recently been shown that saponin acts more powerfully on the red 
blood corpuscles in the absence of serum and that the stromata of the 
corpuscles are the parts affected and not the haemoglobin ; finally, it 
appears extremely probable that the haemolysis is due to the affinity 
of saponin for the cholesterin and other lipoids of the corpuscles, the 
changes in the physical condition of the cholesterin through the per- 
meation of the glucoside resulting in the rupture of the cell and the 
liberation of the haemoglobin. The serum retards the action of sapo- 
nin on the corpuscles by fixing some of it in combination with its lipoid 
constituents (Ransom, Hedon). 

The circulation in mammals is comparatively little affected until 
just before death, when the blood-pressure falls rapidly and the 
pulse becomes weak and slow. The heart continues to beat for 
a short time after the respiration ceases, but is very weak, and finally 
stops, even although artificial respiration is maintained. The isolated 
frog's heart is paralyzed by sapotoxins in the same way as the isolated 
muscle. 

In many experiments, death would seem to be caused by collapse fol- 
lowing the changes in the alimentary canal. In others, however, when 
only small quantities of the poison have been injected, no such changes 
are observed, but the animal dies after a few days, presenting no dis- 
tinct symptoms except general weakness and depression. On the 
other hand, very large quantities injected into a vein may prove fatal 
within a few minutes, and here again no symptoms of intestinal action 
may appear. It is therefore believed that in addition to their irritant 
effects these bodies have a special action on the central nervous system, 
although it is impossible at present to specify its nature. The respira- 
tion is in all cases the first vital function to be suspended. Sapotoxin 
applied directly to the spinal cord in the frog first provokes convulsive 
twitching and clonic spasms and then paralyzes the animal, but it may 
be questioned whether it would have the same effect when carried in 
the blood. 

The sapotoxins are poisonous to invertebrates apparently, unless they 
are protected by a shell, through which they can not penetrate. Thus 
the amoeba and other simple organisms cease their movements, while 
intestinal worms are first excited and then paralyzed in the presence 
of some of the group. 

It has been suggested that the action of the sapotoxins on proto- 
plasm is due to their acting on the proteids, and in some cases a pre- 
cipitation of albumin occurs. But the majority of these bodies do not 
appear to affect the isolated proteids, but only the living substance. 



SAPONIN, SAPOTOXIN AND SOLANINE. 355 

Preparations. 

Quillaja (U. S. P.), Quillaise Cortex (B. P.), Panama bark, Soap bark, the 
inner bark of Quillaja saponaria. 

Tinctura Quillajse (U. 8. P.), Tinctura Quillaise (B. P.), 2-4 c.c. (30-60 
mins.). 

Sarsaparilla (U. S. P.), the root of Smilax officinalis, S. medica, S. papy- 
racea and of other species of Smilax. 

Decoctum Sarsaparillse Compositum (U. S. P.) contains, besides sarsaparilla, 
sassafras, guaiac, liquorice and mezereum. 100 c.c. (3-4 fl. oz.). 

Extractum Sarsaparillse Fluidum (U. S. P.), 4 c.c. (1 fl. dr.). 

Extractum Sarsaparillse Fluidum Compositum contains the same constituents 
as the decoction, except guaiac. 4 c.c. (1 fl. dr.). 

Syrupus Sarsaparillse Compositus (U. S. P.) contains liquorice, senna and 
the oils of sassafras, anise and wintergreen. 10-15 c.c. (2-4 fl. drs.). 

Sarsae Radix (B. P.), sarsaparilla, the dried root of Smilax ornata, im- 
ported from Costa Rica and known as Jamaica sarsaparilla. 

Liquor Sarsse Compositus Concentratus (B. P.) is formed from sarsaparilla, sas- 
safras root, guaiacum wood, liquorice and mezereum. 2-8 fl. drs. 

Extractum Sarsse Liquidum (B. P.), 2-4 fl. drs. 

Senega (U. S. P.), Senegse Radix (B. P.), the root of Polygala Senega. 

Extractum Senegse Fluidum (IT. S. P.), 0.5-1 c.c. (10-15 mins.). 

Syrupus Senegse (U. S. P.), 4-8 c.c. (1-2 fl. drs.). 

Tinctura Senegse (B. P.), J-l fl. dr. 

Liquor Senegse Concentratus (B. P.), |-1 fl. dr. 

Infusum Senegse (B. P.), J-l fl. oz. ; as a draught, 2 fl. oz. 

Caulophyllum (IT. S. P.), Blue Cohosh, the rhizome and roots of Caulo- 
phyllum thalictroides. It contains a saponin substance, to which it prob- 
ably owes any virtues which it may possess. 

Hemidesmi Radix (B. P.), the dried root of Hemidesmus Indicus. 

Syrupus Hemidesmi (B. P.), ^-1 fl. dr. 

Dulcamara (U. S. P.), bittersweet, the young branches of Solanum dul- 
camara. 

Extractum Dulcamarse Fluidum, 4 c.c. (1 fl. dr.). 

Therapeutic Uses. — The drugs of this group are all quite superfluous. 
They may be used to increase the bronchial secretion in cough through 
the nausea caused by their slight irritant action in the stomach, but they 
have no advantages over such drugs as ipecacuanha or apomorphine ; 
the syrup of senega is often prescribed in expectorant mixtures for 
this purpose. Sarsaparilla has been supposed to have an obscure 
action on the nutrition, and has some reputation in the treatment of 
syphilis, but there is no reason to believe that it is of any service here 
or in any other condition, although it may be used as a vehicle for the 
administration of mercury and iodide of potassium. For this purpose 
the compound syrup U. S. P. or compound liquor B. P. is the best 
preparation. Quillaja has been used to some extent as an expectorant, 
more largely to form emulsions and to suspend insoluble powders. Its 
poisonous action ought, however, to preclude its use for this purpose. 
It is frequently stated that members of the sapotoxin series are anti- 
dotes in digitalis poisoning ; but this is founded on experiments in which 
both drugs were applied directly to the frog's heart, and there is no rea- 
son to suppose that they would oppose each other in man, especially if 
given by the mouth, as sapotoxin is absorbed only with great difficulty. 



356 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

Dulcamara has been used to a limited extent as a sedative and hyp- 
notic and also as a diuretic and diaphoretic and in some skin diseases. 
It does not seem to possess any properties which would render it of 
value in medicine, and might well be dispensed with. 

Another series of bodies resembling the saponin series in their effects are 
known as Solvines, Oleites, Polysolve, etc., and are derived from oleic and 
other similar acids by the action of sulphuric acid. The best known is that 
formed from ricinoleic acid. According to Kiwull, solvines have the same 
destructive action as sapotoxin. They have been used in medicine to form 
emulsions, but their use here is to be deprecated on the same grounds as 
that of quillaja. 

Bibliography. 

Robert. Arch. f. exp. Path. u. Pharm., xxiii., p. 233. 
Stewart. Journ. of Exp. Med., vi., p. 257. 
Hedon. Arch, internat. de Pharmacodyn., viii., p. 381. 
Ransom. Deutsch. med. Woch., 1901, p. 194. 

Rachorukow, Atlass u. Tufa/now. Arbeiten a. d. Pharm. Inst, zu Dorpat, i. 
Kruskal. Ibid., vi., p. 1. 
Kiwull. Ibid., iii., p. 1. (Solvin. ) 
Schulz. Ibid., xiv., p. 1. 
Solanine. 

Husemann u. Balmanya. Arch. f. exp. Path. u. Pharm., iv., p. 309. 

Perles. Ibid., xxvi., p. 88. 

Meyer u. Schrniedeberg. Ibid., xxxvi., p. 361. 

Pjuhl. Deutsch. med. Woch., 1899, p. 753. 

Weil. Arch. f. Hygiene, xxxviii., p. 330. 

XXII. ASPIDOSPERMA, OR QUEBRACHO. 

The bark of Quebracho bianco (Aspidosperma quebracho) contains a num- 
ber of alkaloids which are probably very similar in chemical composition and 
which seem to possess almost the same action. They are Aspidospermine, 
Aspidospermatine, Aspidosamine 1 Hypoquebrachine, Quebrachine and Quebracha- 
mine. Another species of Aspidosperma, Payta, contains two alkaloids, Pay- 
tine and Paytanine, of which Paytine resembles closely the Quebracho alka- 
loids in its pharmacological action. 

These alkaloids all produce nausea but even after large doses vomiting 
does not occur except after Aspidosamine. The nausea is accompanied by 
the usual concomitant symptoms — salivation, increased secretion of mucus 
in the respiratory tract, depression and alternately rapid and slow pulse. 
Large quantities often cause symptoms of central nervous stimulation, tonic 
contractions and convulsions. The respiration is quicker and deeper after 
small quantities, but after lethal doses becomes slow and weak, and finally 
ceases. Periodic respiration often occurs before the final standstill, a series 
of deep dyspnceic movements alternating with several shallow, insufficient 
ones. The failure of the respiration is the cause of death in mammals, the 
heart continuing to contract for some time longer. After Aspidosamine, 
there is no stage of quick and deep respirations, but the breathing is rendered 
slow at once and soon becomes periodic. 

These symptoms are generally ascribed to a direct action on the central 
nervous system, which is first stimulated and then depressed. The chief 
seat of action seems to be the medullary centres and the spinal cord, although 
the basal ganglia may also be more or less involved. The stimulation of the 
medullary centres explains the nausea and vomiting and also the changes in 
the respiration, while the convulsions and increased reflex excitability point 
to the spinal cord. 

The terminations of the motor nerves in voluntary muscles are paralyzed 



QUININE. 357 

by aspidosamine and quebrachine in the frog, not by the other alkaloids ; but 
all of them lessen the strength of muscular tissue and eventually paralyze it 
in these animals. Neither of these results has been observed to follow the 
injection of the alkaloids in mammals. 

The circulation in mammals is affected indirectly through the nausea, and 
the heart may be slowed by very large doses ; in the frog the heart is weak- 
ened and eventually paralyzed in the same way as the other muscular organs. 

Eloy and Huchard observed diarrhoea and an increased secretion of urine 
occasionally follow the administration of the alkaloids, and they also describe 
a curious coloration of the blood which they ascribe to a diminution of the 
haemoglobin. Penzoldt attributed the asphyxia to changes in the red cells, 
but the subject of the action of these alkaloids on the blood requires further 
investigation. 

None of the quebracho alkaloids is very poisonous, but of the series que- 
brachine is the most toxic, and aspidosamine and aspidospermatine follow it 
closely. Aspidosp ermine, quebrachamine and hypoquebrachamine are com- 
paratively weak. 

Preparations. 

U. S. P. — Aspidosperma, Quebracho, the bark of Aspidosperma Que- 
brachoblanco. 

Extractum Aspidosp ermatis Fluidum, 1-4 c.c. (15-60 mins.). 

Commercial v ' aspidospermine " is a mixture of all the alkaloids along 
with other bodies. It is sometimes prescribed in doses of 1-2 mgs. (eV-^o gr.). 

Aspidosperma was advised by Penzoldt in the treatment of dyspnoea from 
a variety of causes, and his statements have received a certain amount of 
support from clinicians. The special conditions in which it has been advised 
are dyspnoea from pulmonary disease, especially emphysema, and from car- 
diac weakness and asthma. Its action on the respiratory centre may ex- 
plain to some extent the benefits derived from it, but the increased secretion 
of the bronchi produced by the nausea may also be of some importance. 

It has also been employed as an antipyretic, and has been shown by Eloy 
and Huchard to lower the temperature in animals. 

Bibliography. 

Harnack u. Hoffman. Zeitschr. f. klin. Med., viii., p. 471. 
Eloy u. Huchard. Arch, de Phys. [3], vii., 1886, p. 236. 
Gutmann. Arch. f. exp. Path. u. Pharm., xiv., p. 451. 

XXIII. QUININE. 

The barks of various species of Cinchona and Remijia (Cuprea) con- 
tain numerous alkaloids which seem to resemble each other closely in 
their chemical and pharmacological properties. The best known of 
these are Quinine, Qainidine, or Conquinine, Cinchonine and Cinchoni- 
dine; the others, amounting to some twenty in number, are believed 
to resemble these in their effects on the organism, but very little has 
been done to determine this, and nothing is known regarding their 
relative activity. 

The cinchona alkaloids are derivatives of quinoline. Cinchonine 
and cinchonidine are isomeric (C 19 H 22 N 2 0) and perhaps contain two 
quinoline molecules, while quinine and quinidine (C 20 H 24 N.,O 2 ) are 
methoxyl compounds of cinchonine. 1 

! The other alkaloids of this series which have been identified are homocinchonidine, 
conquinamine, quinamine, cusconine, concusconine, aricine, cusconidine, cuscamine, 
cuscamidine, hydroquinine, hydroquinidine, hydrocinclionine, cinchonaniine, quaint- 



358 ORGANIC DRUGS ACTING AFTER ABSORPTION 

Cinchona bark contains besides these alkaloids several acids, includ- 
ing tannins, and some neutral substances. 

The cinchonas are natives of Western South America, but are now 
cultivated in India and Java. It seems questionable whether the vir- 
tues of the bark were known by the native Indians before the invasion 
of the Spanish, and its introduction into medicine dates from about 
1630-1640 j its name bears testimony to its efficacy in the case of the 
Countess of Chinchon in 1638. 

Action. — Quinine differs from most of the other important alkaloids 
in acting not on some specialized form of living matter, but on the gen- 
eral nutrition of almost all forms of protoplasm. Other alkaloids, such 
as strychnine, are also possessed of similar effects as regards nutrition, 
but their strong affinity for, and intense action on some special tissue, 
prevent their effects on the fundamental properties of living matter 
from being elicited in the higher animals. Quinine is therefore often 
termed a protoplasm poison because its action extends with but little 
variation throughout most forms of living matter ; on the other hand 
the marked effect of strychnine on the nerve cell causes it to be classed 
among nerve poisons, although in organisms devoid of a nervous sys- 
tem it resembles quinine in its effects. The effects of quinine on pro- 
toplasm generally consist in transitory augmentation of its activity, 
followed by depression and death. 

The action of quinine on Undifferentiated Protoplasm, such as is 
found in the unicellular organisms and in the ovum, is therefore of 
greater interest than that of most alkaloids. Binz found that while 
very minute quantities sometimes increase the movements of the amoeba 
and infusoria at first, large amounts paralyze them immediately, and 
the protoplasm assumes a darker granular appearance. The rhythmic 
movements of ciliated organisms are rendered slow and finally arrested 
by very dilute solutions. The microbes of putrefaction are also acted 
upon by quinine, although they seem more resistant than the protozoa ; 
still, quinine solutions have considerable antiseptic power, equalling 
that of carbolic acid, according to some observers. The alcoholic, 
lactic and butyric fermentations are retarded, or entirely prevented 
by quinine through its effects on the organisms, but it is apparently 
devoid of action on some of the lower forms, for moulds (Penicillium) 
grow freely in solutions of the salts ; so that the alkaloid seems to have 
a selective action here, such as is observed also in its effects on the 
ferments of the higher animals. Another example of its action on the 
vegetable cell is that discovered by Darwin in some insectivorous 
plants (Drosera), in which the movements seem to be first excited and 
later paralyzed by the quinine salts. 

The influence of quinine on the reproductive cells of animals has 
been carefully studied by O. and R. Hertwig, who found that both the 

mine, conquairamine, quairamidine and conquairamidine, while several others are 
said to have been separated by some authorities, but are rejected by others. The acids 
generally acknowledged to be present in cinchona are quinic, quinovic, quinotannic, 
quinovatannic, caffeotannic and oxalic, while the neutral bitter substances have been 
named quinovin, quinova-red and cinchona-red. 



QUININE. 359 

spermatozoon and the ovum of the sea-urchin are injured by the addi- 
tion of quinine to the sea- water, the movements of the former being 
paralyzed, and the stages preceding impregnation in the latter progress- 
ing more slowly, or actually retroceding. When quinine is applied 
after the male nucleus has entered the ovum, the complete conjugation 
is delayed and the whole process is rendered abnormal by the admis- 
sion of several spermatozoa. Quinine applied still later prevents or 
delays the division of the ovum through its effects both on the nucleus 
and on the general protoplasm of the cell. 

The individual cells of more complex organisms are affected in the 
same way as these more simple ones. This was first demonstrated in 
the leucocytes by Binz, and after some opposition has been generally 
accepted. When a drop of blood is examined under the microscope, 
the white cells are observed undergoing constant changes of form and 
position exactly similar to those of the amoeba, but minute quantities 
of a quinine salt are sufficient to stop all movements at once, and the 
leucocytes assume a spherical form, become darker in color and gran- 
ular, and soon break up into debris. In the blood vessels similar 
changes occur when quinine is applied locally, as to the frog's mesen- 
tery ; the leucocytes again become darkly granular, and ceasing their 
creeping movements, are carried along by the current much more rap- 
idly than usual. They are no longer observed to push their way through 
the vessel walls, and if they have already penetrated into the tissues 
their movements are arrested. If irritation be applied to the part, no 
such accumulation of leucocytes occurs in the tissues as in the unpoi- 
soned animal, and if an irritant has been applied first and the leuco- 
cytes have poured out of the vessels before the quinine is applied, the 
process is arrested at once on its application. This effect was explained 
by Binz as due to the poison acting on the leucocytes, and although 
attempts have been made to explain it by some change produced on 
the vessel wall by the drug, there now seems no reason to question the 
correctness of his view. Similar results are observed when the drug 
is not applied locally, but carried to the part by the vessels ; the move- 
ments of the leucocytes in the vessels are less distinct ; they are carried 
along passively in the general current, assume a spherical form, and 
have much less tendency to escape into the general tissues, and at the 
same time the number of the leucocytes in the blood undergoes a con- 
siderable diminution. It would be unjustifiable to infer from these 
experiments that the therapeutic dose of quinine inhibits the move- 
ments of the white blood cells in the human body, and it is no part of 
Binz's theory that this occurs. The effect of quinine on the leucocytes 
is merely an example of its effects on the tissues generally. At the 
same time, the number of leucocytes in the human blood is diminished 
by ordinary quantities of quinine, showing that the action on the frog's 
leucocytes extends also to those of man, even when the quinine is ab- 
sorbed from the stomach and intestine. 

Other evidence of the action of quinine is gained from processes 
which may be regarded as due to Unorganized Ferments. 



360 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

Thus the oxidizing action of drawn blood was shown to be dimin- 
ished in several experiments performed by Binz. Immediately after 
its issue from the vessels the unpoisoned blood undergoes a diminution 
of its alkalinity, from the oxidation of some unknown substances at 
the expense of the oxyhemoglobin, which is partially reduced. This 
acid fermentation is prevented by the addition of quinine to the blood. 
Even when pieces of tissues are added and the reduction of the arterial 
blood would ordinarily be much accelerated, quinine prevents or retards 
the change. A similar inhibition of the oxidizing action of the blood 
is shown by its failure to form the blue oxidation product of guaiac, 
or to decolorize indigo when it is applied to it along with quinine. 1 
Or instead of blood a slice of potato or a watery extract of a liv- 
ing plant may be used. From these experiments the inference i- 
drawn that quinine hinders the action of the oxidizing ferment of the 
blood and tissues. On the other hand, Jacquet found that it had little 
or no effect on the oxidation of substances passed through the vessels 
of excised organs. Another ferment action which is said to be retarded 
by the presence of quinine is the coagulation of the blood. The gastric 
and pancreatic ferments are also said to be rendered less active by the 
addition of quinine in artificial digestion experiments (Rossbach), 
while the ptyalin of the saliva, emulsin and diastase are unaffected 
(Binz). 

These experiments indicate that quinine hinders some, if not all, of 
the processes which normally occur in living matter, and which are 
expressed in movement and in various chemical products ; they indi- 
cate in addition that this action is not confined to the intact protoplasm, 
but extends to some of the ferments. When very minute quantities 
of the drug are applied, the stage of depression is sometimes preceded 
by one of augmented activity. Rossbach found that quinine and 
several other alkaloids exercise some influence on solutions of the 
proteids, which coagulate at a lower temperature than usual, but it is 
impossible to determine at present whether this fact is connected with 
their effects on living tissue or is merely a coincidence. 

Among the Vertebrates, also, small quantities of quinine give rise 
to disturbances of the nutrition, but before discussing these, it may 
be well to indicate the symptoms induced by poisonous doses. 

• In the frog, a short stage of increased reflex excitability is followed by 
the loss of spontaneous movements, the arrest of respiration and paralysis 
of the spinal cord. In mammals, the spinal cord is said to be stimulated by 
small quantities and then to be depressed. The respiration is sometimes 
accelerated in the beginning, but is afterwards weakened, and its failure is 
the cause of death. General depression and muscular weakness are usually 
the only cerebral effects noted, and the tremor and convulsions said to occur 
in some instances may be due to the use of impure quinine. The heart is 

1 The well-known guaiac experiment is performed as follows : A fresh solution of 
guaiac resin in alcohol, to which some peroxide of hydrogen has been added, is 
divided into two parts. To the one a minute quantity of quinine is added, and one or 
two drops of blood are then allowed to flow into each part. The one containing the 
quinine remains uncolored, while the other assumes a blue tint from the oxidation of 
the guaiac by the unpoisoned blood. 



QUININE. 361 

often accelerated at first, but is afterwards slow and weak, while the blood- 
pressure, after a slight increase, declines progressively. According to ISan- 
tesson, quinine given by the stomach has comparatively little effect on the 
heart and blood-pressure in mammals. These symptoms point to a prelimi- 
nary stage of stimulation, followed by depression of the Central Nervous 
System and heart in the vertebrates, corresponding to the two stages ob- 
served in the simpler organisms. They are only elicited by very large 
quantities of the drug and have perhaps received greater attention than they 
merit at the hands of experimental pharmacologists. The depression of the 
reflexes of the frog was at one time attributed to a stimulation of the in- 
hibitory centres of Setschenow, and this was supported by the fact that it 
could be removed at first by division of the medulla oblongata. It seems 
more probable, however, that the local irritation of the acid salts usually 
injected caused the temporary depression indirectly, and that the action on 
the central nervous system consists in a transient stimulation followed by 
lasting depression. The statement that the depression is due to the weak- 
ness of the heart seems incorrect. 

The changes in the Circulation in mammals are caused by a preliminary 
contraction of the arterioles and acceleration of the heart, followed by dila- 
tion of the former and slowing and weakening of the latter. In both cases 
the action is probably a direct one on the muscle of the arterioles and heart, 
although some investigators consider the acceleration due to depression of 
the inhibitory mechanism in the heart or in the medulla oblongata. The 
effects of quinine on the isolated frog's heart have been studied carefully by 
Santesson, who found that the action was entirely muscular and consisted 
in slowing, accompanied by marked decrease in the strength of the contrac- 
tions. 

In fatal poisoning in mammals the heart is generally very much weakened 
when the respiration ceases, but continues to beat for some time afterwards. 

Quinine acts upon Muscle in the same way as upon the simple organisms, 
temporarily increasing its power and subsequently weakening it. Thus 
Santesson found that the strength of the individual contractions was in- 
creased, and that a contraction occurred against greater resistance than 
normally, but wiien the stimulation was repeated, fatigue set in sooner than 
in the unpoisoned muscle. Large quantities of quinine throw the muscle 
into rigor, which resembles that produced by caffeine, and is probably asso- 
ciated with its action in accelerating the coagulation of myosin (Furth). 

The Nerve Trunks are said to be remarkably tolerant to solutions of qui- 
nine, which do not lessen their irritability when applied locally in sufficient 
quantity to cause marked abnormalities in the muscular contraction. No 
sufficient evidence has been brought forward that quinine affects the periph- 
eral ends of the motor or sensory nerves. The number of Leucocytes in the 
blood is much diminished by the administration of quinine in man and the 
lower mammals, but it is unknown how this is effected. The statement that 
the normal Spleen undergoes a contraction in size and partial atrophy after 
quinine, while not improbable in itself, is not supported by experiments in 
which accurate methods were used. 

A slight increase in the amount of Urine excreted has been observed some- 
times, but does not seem constant. It is attributed to the action of the qui- 
nine on the renal epithelium, by which it is excreted. The other secretions 
do not seem to be altered by quinine unless it is applied directly to the cells 
in large quantity by injecting solutions into the duct of the gland. The 
statement is made that the glycogenic function of the liver is altered so that 
less sugar than usual is supplied to the blood, and there is some evidence 
that other hepatic functions are less active than usual. 

Cinchona preparations and quinine have the same action on the appe- 
tite and digestion in man as the simple bitters and mix vomica. Or- 



362 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

dinary therapeutic doses often produce no very obvious symptoms, the 
most frequently observed effect consisting in derangement of the Sense 
of Hearing, less frequently of that of Sight. Ringing or roaring sounds 
in the ears, accompanied by slight deafness, are produced by moderate 
quantities and large doses are not infrequently followed by complete 
loss of hearing for a time. Contraction of the field of vision is ob- 
served less often, but in some cases total blindness has been produced 
and has lasted for several days or even weeks. Color-vision is es- 
pecially liable to be rendered imperfect or temporarily paralyzed by 
quinine. There is every reason to believe that the defects of hearing 
are due to congestion of the auditory canal and not to any brain effects, 
for congestion of the membrana tympani has been observed in several 
cases in man, and Kirchner has produced congestion, inflammation and 
ecchymosis in the tympanum and labyrinth of animals by the adminis- 
tration of quinine. This inflammation may become chronic and pro- 
duce lasting impairment of hearing. On the other hand, the disorders 
of sight are accompanied by a very marked contraction and even oblit- 
eration of the retinal vessels, which may be followed by degenerative 
changes in the retinal nerve cells and in severe cases by some atrophy 
of the optic nerve. No explanation has been offered for these opposing 
vascular effects in the ear and eye. Quinine possesses some irritant 
action which betrays itself in discomfort in the stomach and eructation 
after large and repeated doses by the mouth, and by pain and tender- 
ness when it is injected subcutaneously ; but this drawback is not of 
so much importance as in the case of many other drugs. 

Large doses of quinine produce some confusion and depression with 
a sense of fulness and heaviness in the head from their action on the 
Cerebrum, and this is sometimes accompanied by uncertain gait and 
slow pulse. Very few cases of fatal poisoning have been satisfactorily 
determined to be due to quinine, although a considerably larger num- 
ber have been attributed to it. In these cases marked weakness of the 
heart and collapse accompanied by loss of sight and hearing, muscular 
weakness, apathy, slow, gasping respiration and finally unconscious- 
ness and total failure of the respiration were observed. In some cases 
delirium and convulsions have been noted, but it may be doubted 
whether the preparation did not contain other members of the cin- 
chona alkaloids. Enormous doses of quinine sulphate have been 
swallowed without any serious results. Thus in one case thirty 
grammes (one ounce) produced only some confusion and noises in the 
ears. Probably only a small quantity of the drug was absorbed, as 
the sulphate, which is generally used, is exceedingly insoluble. 

The extensive use of quinine in therapeutics has demonstrated that 
many persons have curious Idiosyncrasies in regard to it. This is be- 
trayed in many cases by the development of ear symptoms after com- 
paratively small doses, but in others symptoms arise which do not 
appear in the great majority of people even after large doses. The 
commonest of these are skin eruptions, of which a large variety have 
been described, and which can be distinguished from ordinary diseases 



QUININE. 363 

of the skin only by the history or by the detection of quinine in the 
urine and other excretions. These exanthemata are often accompanied 
by some rise in temperature, which has received more attention than 
it appears to deserve, for it is rare and even when present is of insig- 
nificant extent. Other less important effects, which have been occa- 
sionally noted, are gastric discomfort and diarrhoea, while albuminuria 
and hsematuria have been met with in a very few cases and haemor- 
rhages from various surfaces have been noted occasionally. 

The action of quinine on the Uterus is the subject of a large number 
of memoirs, but is still quite uncertain. Abortion certainly occurs 
occasionally after its use in malaria, while in other cases labor pains 
may be induced by quinine. Many physicians use it during labor if 
the pains cease or if they seem to be too weak to expel the child. But 
opinions differ as to its efficiency, for while some regard it as the most 
useful of remedies for this purpose, others have found it to fail in the 
great majority of cases and regard this action as an idiosyncrasy con- 
fined to a small proportion of individuals. It is quite impossible to 
state how quinine acts here, but is seems most likely that the uterine 
muscle is affected directly. 

In the Alimentary Tract, quinine and the cinchona preparations act 
in the same way as the simple bitters (page 56). Quinine delays 
proteolysis in experiments in artificial digestion. 

The constant effects of quinine on the Metabolism, which are pro- 
duced by quantities of the drug too small to have any further action 
except in specially susceptible individuals, are of much greater interest 
and importance than the symptoms already mentioned. This alteration 
of the tissue change occurs throughout the mammalia, and consists in a 
marked diminution in the destruction of the nitrogenous constituents 
of the tissues. After the administration of quinine, the nitrogen in the 
urine is found at first slightly augmented for a few hours, but then un- 
dergoes a diminution of considerable extent, due to a restricted produc- 
tion of all the nitrogenous constituents of the urine, but especially of the 
urea and the uric acid. The latter might be expected to be lessened from 
the diminished number of leucocytes in the blood, while the falling 
off in the urea and total nitrogen and sulphur indicates that the 
metabolism of the proteid tissues in general is retarded by quinine. 
The phosphates and sulphates undergo a corresponding alteration, but 
all of the metabolic changes are not affected by quinine, for the car- 
bonic acid exhaled and the oxygen absorbed by the lungs present no 
marked alteration in amount, so that the oxidation of the tissues can- 
not be said to be altered, but only the breaking down of the nitroge- 
nous bodies. This absence of effect on the oxidation of the body is not 
what might have been expected from the experiments of Binz and 
others on the simpler tissues, for these showed that oxidation of all kinds 
was retarded by quinine. On the other hand, it corresponds with Jac- 
quet's experiments on the oxidizing ferment of the tissues, and has been 
attested by too many observers to allow of any doubt as to its correct- 
ness. In the case of several other drugs the diminution of the urea is 



364 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

compensated for by the increase in the other nitrogenous bodies in 
the urine, but the fall in the total excretion of nitrogen after quinine 
points to an alteration of the metabolism of the body in general, and 
not to the paralysis or destruction of the organs which change the 
first products of the nitrogenous metabolism to the simpler forms in 
which they are finally excreted. The oxygen absorbed and the car- 
bonic acid excreted by the tissues are generally held to measure the 
amount of work done and heat formed by the muscular and other 
movements of the body, and quinine therefore does not seem to affect 
these functions, while it would appear that some other processes, per- 
haps the death, growth and repair of the tissues, are less active than 
normally. At any rate the nitrogenous food is not dissipated so rap- 
idly, but is stored up in the body in some unknown form, for v. Noorden 
found that under constant diet the nitrogen excretion diminished under 
quinine and this diminution continued for two days after the treat- 
ment was stopped. The nitrogen absorbed from the alimentary canal 
remained unchanged, and a certain amount of proteid food must there- 
fore have been added to the body and saved from the decomposition 
which it would have undergone in ordinary circumstances. 

The influence of quinine on the metabolism is closely connected 
with its effects on the body Temperature. It was early observed that 
besides its specific effects in malaria, quinine often depressed the tem- 
perature and improved the condition in a number of other fevers. This 
was long supposed to be due to some action that it exercised on the 
central nervous system, but when the nervous theory of fever fell into 
disrepute, this explanation also came to be looked upon with suspicion, 
and was finally disposed of by the experiments of Binz and others, who 
showed that quinine lowered the fever temperature after division of 
the spinal cord. Binz therefore attributed the antipyretic effects of 
quinine to its direct action on the tissues, and this explanation is gen- 
erally held to be correct. It is to be remarked that while there is no 
question as to the reduction of the temperature effected by quinine in 
many cases of fever, it has little effect upon the normal temperature. 
In some cases a slight fall in the thermometer is observed, but it is 
never very considerable, and often no results follow its administration, 
or a rise of 0.1-0.2° C. may occur. 

Gottlieb found that the fever temperature produced in rabbits by 
injury of the region of the corpus striatum was reduced by quinine, and 
that the regulation of the heat production according to the temperature 
of the surrounding air was not impaired by it. Thus, when the tem- 
perature of the cage was kept at about 30—32° C, and animals poisoned 
with morphine and some other drugs had fever temperature, the rab- 
bit to which quinine had been administered, showed little change from 
the normal. From this he infers that the heat-regulating mechanism 
of the brain is not affected by quinine, and that the reduction of tem- 
perature, when it occurs at all, is due to alteration in the metabolism. 
In a later research the same author found by calorimetric experiments 
that the warmth production was lessened by quinine, both in normal 



U1N1NE. 



365 



animals and in those in which fever had been induced by injury of the 
corpus striatum. This lessened production is accompanied by a less- 
ened output of warmth, as occurs in unpoisoned animals when for any 
reason the heat formation is retarded. The lessened heat formation 
after quinine he again regards as evidence of its effects on the meta- 
bolism. 

This explanation of the antipyretic effects of quinine is not without 
difficulties, however. As has been stated above, the modern theory of 
warmth production in the body is that the oxidation of the carbon com- 
pounds is the chief if not the 
only source of heat ; but quinine 
does not lessen the amount of 
oxygen absorbed nor of carbonic 
acid excreted by the lungs, as it 
might be expected to do if it 
acted only through the metabo- 
lism, and this has led some inves- 
tigators to deny that the heat pro- 
duction is lessened in the body. 
This reduces the antipyretic ac- 
tion of quinine to a paradox ; on 
the one hand, there is no question 
that the temperature falls, while, 
on the other hand, the combustion 
is certainly not reduced to any 
notable extent, and at the same 
time there is no reason to suppose 
that the output of warmth is in- 
creased. 1 While no solution of 
this dilemma has been offered as 
yet, it seems extremely probable 
that the antipyretic action of 
quinine is due to its retarding the 
metabolism ; it has been suggest- 
ed that while the combustion in 
the normal tissues is not affected 
by quinine, the presence of fever 
poisons throws them into a state of augmented activity in which 
they are more susceptible to its sedative action, and that even in 
the normal organism a reduction of the temperature might be in- 
duced if sufficient of the drug could be ingested without exciting 
other symptoms. In this connection it is of interest to remember that 
in fever the nitrogenous decomposition is much increased, while quinine 
has a directly opposite effect. The diminution in the nitrogenous 
metabolism may also lead to an increased resistance being offered by 

a It is true that Maragliano states that quinine dilates appreciably the peripheral 
vessels in fever ; but as it has the same effect in health this dilation cannot be held to 
explain the fall in temperature, for in health quinine has no such antipyretic action. 





Fig. 


33. 






,-J 


^ 




/ 


\ 




/ 


\ 

N 




i 
i 


n 






J\ 








\ r L 


- 



AH Q B 

Diagram to illustrate the relation of the warmth 
output and internal temperature (after one of Gott- 
lieb's experiments). The unbroken line represents 
the changes in the warmth output, which may be 
estimated by measuring its distance from the ab- 
scissa AB. The dotted line represents the internal 
temperature. From A to H, normal. Ativan in- 
jury to the brain caused a marked diminution in 
the heat output and a corresponding rise in the in- 
ternal temperature. At Q quinine was administered 
and was followed by an immediate fall in the inter- 
nal temperature, while the heat output was practic- 
ally unchanged. Contrast Fig. 35. 



366 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

the tissues to the cause of the fever, or may lessen the poisonous pro- 
ducts circulating in the blood. In addition, the microbes of fever may 
themselves be rendered less active by the drug, although this antiseptic 
action would appear to be of subordinate importance, as many of the 
pathogenic forms have been found to offer great resistance to it. 

Quinine has much more effect in reducing temperature when it is 
administered in the beginning of a natural remission than when it is 
given during a rise of the thermometer. This property is shared by 
most antipyretics and will be treated of at greater length under the 
antipyrine series. 

Excretion. — Quinine appears in the urine within a short time (30 
minutes) after its exhibition by the mouth, and about one half of the 
quantity absorbed is excreted within six hours. After this it passes 
out of the body more slowly, and traces may be detected in the urine 
seventy-two hours after its administration. In some fevers the ex- 
cretion is said to be considerably retarded. Kerner found that some 
of the quinine absorbed was partially hydrated in the tissues and ex- 
creted as dihydroxyl-quinine, but if any such change occurs, it can 
affect only a very small proportion of the alkaloid, as over ninety per 
cent, of that ingested has been recovered unaltered from the urine. 1 

Of the Other Cinchona Alkaloids, quinidine or conquinine resembles quinine 
most closely in its effects, which are somewhat weaker, however. Cincho- 
nine, while very similar to quinidine in most points, has some tendency to 
produce convulsions, but this effect is much more liable to occur under cin- 
chonidine which save for its resemblance in other features to quinine, would 
be entitled to be classed among the convulsive poisons. 2 These convulsions 
are of an epileptiform character, and are only produced by very large doses, 
but Albertoni discovered that even small quantities administered to epilep- 
tics increased the number of the attacks. He found that these epileptiform 
seizures were not prevented by the removal of the cerebral cortex in dogs, and 
that the irritability of the motor areas was not altered by cinchonidine, and 
therefore concluded that the poison produced these symptoms by acting on 
some lower division of the central nervous axis. It is believed by many, 
however, that epileptic attacks can be elicited only when the cerebral cortex 
is intact, and although no results directly opposed to those of Albertoni have 
been recorded, the question must still be regarded as an open one. 

In other respects cinchonine and cinchonidine differ from quinine only in 
the degree and not in the kind of their action. Cinchonamine possesses an 
even more marked convulsant action than cinchonidine. 

The effects of the other alkaloids have not been the subject of much in- 
vestigation, but they seem to differ from quinine chiefly in their effects on 
the central nervous system. These are not entirely absent in quinine itself, 
for, as has been stated already, the reflex irritability is at first increased and 
then diminished in both frogs and mammals, and in some cases even con- 
vulsions are stated to have occurred in quinine poisoning, although these are 
so rare that the suspicion is aroused that the preparation was contaminated 
with cinchonidine or some other alkaloid. 

Cinchonidine seems the most poisonous of the four chief alkaloids, quinine 
following next, and then cinchonine and quinidine. 

1 Further investigation regarding the fate of quinine in the human tissues is desir- 
able, since Merkel has found that seven-eighths of that administered to dogs is com- 
pletely oxidized and the remaining eighth undergoes extensive chemical change. 

2 These convulsions are not confined to the vertebrate kingdom, but have also been 
observed in the crab by Langlois and Varigny. 



0.3-1 G. (5-15 grs.); to be increased when 
necessary. 



QUININE. 367 

Pkepaeatioks. 

U. S. P. — Cinchona, the bark of Cinchona calisaya and of C. officinalis 
and of hybrids of these and of other species of Cinchona, yielding not less 
than 5 per cent, of total alkaloids and at least 2.5 per cent, of quinine. 

Cinchona Rubra, red cinchona, the bark of Cinchona succirubra, contain- 
ing at least 5 per cent, of alkaloids. 

Infusum Cinchonx, 60 c.c. (2 fl. oz.). 

Extractum Cinchona, 0.5-2 G. (10-30 grs.). 

Extractum Cinchonx Fluidum, 4 c.c. (1 fl. dr.). 

Tinctura Cinchonas, 4-15 c.c. (1-4 fl. drs.). 

Tinctura Cinchonje Composita is the only preparation of red cinchona, 
and contains in addition serpentaria and bitter orange peel. 4-15 c.c. (1-4 
fl. drs.). 

These preparations of cinchona were formerly much more in vogue than 
at the present day, in which they have been replaced for most purposes by 
the alkaloids. They are still prescribed alone or together with other reme- 
dies as stomachic bitters. 

Quinina, 

Quininse Sulphas, 

Quininx Bisulphas, 

Quininx Hydrobromas, 

Quinine Hydrochloras, 

Quininx Valerianas, 

Ferri et Quininx Citras, 0.3-0.6 G. (5-10 grs.). 

Ferri et Quininse Citras Solubilis, 0.3-0.6 G. (5-10 grs.). 

Syrupus Ferri, Quininse et Strychninx Phosphatum, Easton's syrup, 4 c.c. 
(1 fl. dr.). 

B. P. — Cinchona Rubrae Cortex, red cinchona bark, the dried bark of the 
stem and branches of Cinchona succirubra. It ought to contain 5-6 per 
cent, of total alkaloids, of which one half should consist of quinine and cin- 
chonidine. 

Extractum Cinchonse Liquidum, 5 per cent, of alkaloids, 5-15 mins. 

Tinctura Cinchona, 1 per cent, of alkaloids, J-l fl. dr. 

Tinctura Cinchona Composita, containing bitter orange peel, serpen- 
tary and coloring matters, J-l fl. dr. 

Infusum Cinchonse Acidum, containing aromatic sulphuric acid, ^-1 fl. oz. 

Quininje Hydrochloridum, "J 

Quininse Hydrochloridum Acidum, > 1-10 grs. 

Quininse Sulphas, J 

Tinctura Quininse, formed from the hydrochloride and flavored with orange, 
J-l fl. dr. 

Tinctura Quininse Ammoniata, formed from the sulphate, J-l fl. dr. 

Vinum Quininse, J-l fl. oz. 

Pilula Quininx Sulphatis, 2-8 grs. 

Syrupus Ferri Phosphatis cum Quinina et Strychnina, Easton's syrup. Each 
fl. dr. contains i gr. of quinine sulphate and ^ gr. of strychnine. £-1 fl. dr. 

Ferri et Quininx Citras, 5-10 grs. (See Iron.) 

Quinine is practically insoluble in water and several of its salts are 
only dissolved sparingly. Thus, the sulphate requires 800 times its 
own weight of water, the hydrochlorate 35, the hydrobromate 54, and 
the valerianate 100. The presence of acid in excess renders them 
much more soluble, and the acid hydrochlorate is dissolved in less than 
its own weight of water, the bisulphate in 10 parts. They all form 
crystalline powders with a very bitter taste, and their solutions in 
water have a blue fluorescence when sulphuric acid is present. The 



3G8 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

acid hydrochloride and the bisulphate have an acid reaction, the others 
are neutral. 

The sulphate of quinine is the salt generally prescribed, although 
the hydrochlorate is more soluble and ought to be preferred. The 
hydrobromate and valerianate are comparatively seldom used. Instead 
of the acid salts being prescribed, some sulphuric acid or hydrochloric 
acid may be ordered to be added to the neutral salts in order to facili- 
tate their solution. 

The salts of quinine are frequently given in the form of pills, cachets 
or capsules, which have the advantage of avoiding the bitter taste, but 
from which the alkaloid is more slowly absorbed than from solutions. 
Care must be taken that the pills are soft and freshly prepared, as 
when kept for any length of time they become hard, and in this con- 
dition frequently pass through the bowel unabsorbed. The salts or the 
pure alkaloid may also be given as powders, or the former in solution, 
but these are objected to by many patients on account of the bitter 
taste. When a rapid absorption is desired, solutions should be used, 
flavored, if necessary, with syrup and volatile oils. Solutions of the 
salts are occasionally injected as enemata, but are liable to set up irri- 
tation and be rapidly evacuated. The hypodermic method has also 
been advised in cases of emergency, or where the salt cannot be retained 
or absorbed from the stomach ; for this purpose a solution of the 
hydrochlorate with hydrochloric acid in excess or of the sulphate is 
injected deeply into the muscular tissue. This form of medication is 
painful, but does not seem to induce more serious results if ordinary 
care is used. The neutral hydrochlorate may be dissolved in hot 
water and injected when the solution reaches body temperature with 
less pain than is elicited by other salts. In this way about two parts of 
water are required to dissolve one of quinine. The intravenous injec- 
tion of quinine has been practised by Baccelli with success in cases of 
pernicious malaria. He uses the hydrochlorate in a solution of com- 
mon salt and injects into one of the veins of the arm. 

Many other salts of quinine have been proposed, and have enjoyed a cer- 
tain reputation for some time. Among the better known of these is the 
tannate, which is exceedingly insoluble and almost tasteless, and is prescribed 
in powder in doses of 1-3 G. "Tasteless" quinine seems to be used to 
designate either the tannate or the pure alkaloid. Other salts which have 
been recommended are the tartrate and the lactate. The double hydrochlorate 
of quinine and urea has been used for hypodermic injection and is said to be 
less irritant than the other preparations. Euquinine is the ethyl-ether of 
quinine-carbonic acid (CO(OC 2 H 5 )(OC 20 H 23 N 2 O)) and is said to possess the 
therapeutic virtues of quinine without its bitter taste and without inducing 
ringing in the ears and other symptoms. Quinine is very easily dissolved in 
water when it is mixed with antipyrine in the proportion of three parts of 
quinine to two of antipyrine, and this solution is said to be less painful when 
it is injected hypodermically than others. A chemical combination seems to 
be formed between the natural and the artificial alkaloid (Santesson). 

A famous preparation of quinine is Warburg" 1 s tincture, which has been 
extensively used in India in the treatment of malaria. It contained a very 
large number of ingredients, many of which were certainly entirely super- 
fluous. Among the more important constituents were aloes, rhubarb, 



QUININE. 369 

gentian, camphor, and various volatile oils ; it is possible that some of these 
may have aided the quinine through their effects on the stomach. Various 
drugs, such as capsicum and piperine, have long had some reputation as 
adjuvants in quinine treatment for a similar reason. 
Quinidinse Sulphas, 1 

Cinchonina, [(U.S. P.), 0.5-1.5 G. (8-20 grs.). 

Cinchoninse Sulphas, \ y n 7 

Cinchonidinse Sulphas, J 

These alkaloids have been used occasionally as substitutes for quinine, 
but have somewhat less therapeutic effect, while cinchonidine is more liable 
to produce symptoms of poisoning. They might all be dispensed with, 
without loss to therapeutics. 

Quinoidine and quinetum were formerly used as substitutes for quinine at a 
time when the price of the latter was very high. They were mixtures of the 
other cinchona alkaloids and have fallen into disuse. 

Therapeutic Uses. — The introduction of cinchona into therapeutics 
was due to the discovery of its efficacy in ague or Malaria, and with 
growing experience in the disease and its treatment, the confidence in 
the drug, or rather in its chief alkaloid, has constantly increased, until 
the action of quinine in malaria is now quoted as the best example of 
a specific in therapeutics. The explanation of its action has only been 
arrived at within the last few years with the discovery of the cause of 
malaria, the plasmodium malaria, although in 1868 Binz suggested 
that the then unknown malarial poison was probably rendered inert by 
quinine, The plasmodium belongs to the group of protozoa, and in 
one of its stages comes to resemble somewhat the amoeba, on which 
Binz experimented. The effect of quinine seems similar in the two 
organisms, although it is probable that the alkaloid acts more strongly 
on the malarial organism in the blood than on the common amoeba 
living in water ; another organism closely related to that of malaria 
and found in the blood of birds appears to be unaffected by quinine. 
When quinine is administered to a patient suffering from malaria, the 
organism in the blood breaks up and disappears, leaving only a few 
more resistant forms ; these, however, may continue to grow and mul- 
tiply until they cause a second attack, unless the treatment be continued 
and the surviving organisms, changing into less resistant forms, are 
destroyed by the drug. 

In a drop of malarial blood the plasmodia may be seen in active 
movement, but a minute drop of quinine solution paralyzes and kills 
them, exactly as it kills the amoeba. The explanation of the action of 
quinine on malaria lies in its effects as a protoplasmic poison, therefore, 
which acts more strongly (specifically) on the lower forms of life than 
on the higher, and can consequently be introduced into the human body 
with impunity in doses which are destructive to the simpler organisms 
which may have invaded it. An attempt has been made to explain the 
effects of quinine in malaria by a tonic or strengthening effect on the 
tissues whereby they are rendered more resistant to the invasion, 
but its rapid effects would seem to be more easily explained by a 
specific action on the plasmodium. Experience has shown that qui- 
nine is most effective when it can act immediately after the paroxysms 
24 



370 



ORGANIC DRUGS ACTING AFTER ABSORPTION. 



of ague, and this is now explained by the fact that the organisms are 
in their least resistant form — the amoeboid — at this time. If quinine 
is given at the beginning of an attack, sufficient will remain in the blood 
when the temperature begins to fall to destroy the unprotected spores 
of the parasite, or the same result may be obtained by a dose given as 
the temperature begins to fall provided the drug is rapidly absorbed, 
as is ordinarily the case. It may be ordered in one dose of about 1 G. 
(15 grs.), or in divided doses given at intervals during the fall of the 
temperature. This frequently prevents the next attack, but if any rise 
of temperature occurs, a smaller dose should be administered. After 
this a dose of 1 G. should be given every six days, in order to com- 
plete the destruction of the organisms which have developed from the 



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Temperature chart in a case of malaria in which quinine (10 grains) was administered in the third 
paroxysm as the temperature was falling. On the following day no rise of temperature occurs. 
The temperature was taken every three hours. (Dock.) 

resistant forms left alive after the first administration. Quinine is 
generally administered by the mouth in malaria, but its intensely bitter 
taste renders this treatment disagreeable, and in children and in cases 
of persistent vomiting it may be impossible ; in such circumstances it 
may be given in an enema or suppository, or in children the tasteless 
forms may be employed. In recent years good results have been ob- 
tained by the hypodermic method, and in the severe form known as 
pernicious malaria, Baccelli found the intravenous injection superior 
to any other method of administration. A great deal of weight was 
formerly laid on the use of purgatives and emetics as preliminaries to 
the treatment of malaria with quinine, and the former are undoubtedly 
of service sometimes, although it is unnecessary to delay the quinine 
treatment by waiting for the intestines to be evacuated. 

Quinine is used not only as a remedy, but also as a prophylactic 



QUININE. 371 

against malaria. Its value for this purpose has been attested by long 
experience, but there is still no unanimity of opinion as to the best 
method of administration and the dose required. Plehn found that 
one gramme of the sulphate given in one dose every seven days was 
sufficient to prevent the disease, which is believed to have an incuba- 
tion period of a week, while others recommend doses of 0.1-0.2 G. 
(2-3 grs.) every morning. 

One of the results of quinine medication in early cases of malaria is 
the reduction of the enlarged spleen, and this has led to its use in 
other Diseases of the Spleen with enlargement. In malaria the effect 
on the spleen is only secondary to the removal of the cause of the dis- 
ease, but the action of quinine in lessening the number of leucocytes 
in the blood might explain some alteration in the spleen. In some 
cases of leucsemic enlargement encouraging results have been obtained 
from the continued use of quinine. 

Various other Febrile Conditions have been treated with quinine, 
partly for the sake of its antipyretic effects and partly in the belief 
that it acts as an antiseptic in the blood. As regards its effect on the 
temperature in non-malarial fever, it not infrequently causes a con- 
siderable fall, and has the advantage of possessing a more prolonged 
action and of causing less risk of depression and collapse than the newer 
antipyretics. On the other hand, the fever is not reduced so rapidly 
and generally not to the same extent as by the latter, and the large 
quantities of quinine required are liable to cause discomfort from their 
effects on the brain and hearing. Typhoid fever, scarlatina and other 
acute pyrexias are sometimes treated with quinine for this effect. The 
best results are obtained when it is exhibited in maximal doses when 
the temperature is falling or when it has been temporarily reduced by 
other means, such as cold baths. Perhaps, however, the beneficial ac- 
tion of quinine in those cases ought to be measured not so much by 
the reduction of the body temperature as by the lessened destruction 
of the tissues. It would be interesting to know whether in those 
cases in which quinine treatment is successful, the nitrogen of the urine 
is diminished in proportion to, or in excess of the fall of the tempera- 
ture. In general, antipyrine and its allies have succeeded in ousting 
quinine from its former position as the best of the antipyretics. The 
use of quinine has been recommended in septicaemia, largely from a 
belief in its antiseptic action in the blood. In this connection it is to 
be remarked that the microbes of septic fever are very much more 
resistant to the action of quinine outside the body than are the pro- 
tozoa, and the question therefore arises whether the blood and tissues 
are not liable to be seriously injured by the quantity of quinine re- 
quired to act on the parasites they contain. In many cases of septi- 
cemia in which beneficial results are said to have been obtained by the 
use of quinine, the quantity administered was obviously too small to 
have any effect either on the temperature or on the microbes. 

Quinine has been used in various forms of Neuralgia and Headache, 
especially when they were periodic in their appearance, and good re- 



372 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

suits have been obtained in these cases and also in others where no 
periodicity could be observed. Many of these were certainly not of 
malarial origin, and no explanation of the action of quinine here has 
been proposed. Perhaps the lessened formation of uric acid and other 
poisonous products may be suggested as a possible cause of the im- 
provement. 

The tinctures of cinchona are often prescribed as stomachic bitters 
and for this purpose are generally fortified by preparations of nux 
vomica or of the simple bitters. 

Quinine has been advised in whooping-cough, hay fever and in- 
fluenza, and in fact is regarded by many as a specific in these diseases, 
though others have found it unreliable. It is often difficult to induce 
a child to take the bitter salts, and recourse may be had to the alka- 
loid itself, euquinine, or the tannate disguised with sugar or chocolate. 
The use of a solution as a wash for the nose in hay fever was brought 
into prominence by Helmholtz, who gained relief in this way, but 
it has not proved very efficacious. The local use of quinine solu- 
tions and of cinchona preparations is also advised in relaxed throat 
(gargle) and in gonorrhoea (urethral injection). It has sometimes 
been used as an antiseptic externally, but is too expensive for ordi- 
nary use. 

Quinine has been advised as an ecbolic to increase the contractions 
of the uterus during labor. This was suggested by the observation 
that in malarial regions, abortion occasionally occurred after quinine, 
but many regard this as one of the rarer idiosyncrasies rather than as 
a fact upon which the therapeutic use of the drug is to be based. At 
the same time others report the most satisfactory results from the 
treatment of uterine inertia with quinine, and prefer it to ergot in this 
condition. The movements of the uterus induced are said to be prac- 
tically identical with those occurring naturally. 

Contraindications. — Where a special idiosyncrasy exists, quinine may 
be unsuitable, but these cases are far rarer than is generally believed. 
A moderate action on the hearing, for example, is not to be considered 
a contraindication, although in those cases a small dose is often found 
sufficient in malaria. Where an inflammatory condition of the mem- 
branes of the ear already exists, quinine ought to be administered with 
care, or avoided entirely if possible. The addition of bromides is 
often found to lessen or remove the discomfort arising from the dis- 
ordered hearing, but the quantity of bromide contained in the hydro- 
bromate of quinine is insufficient to effect this, and the ordinary potas- 
sium salt ought therefore to be prescribed. Where very marked 
disturbance of the digestion exists, quinine is often liable to augment it, 
owing to its irritant properties, and must therefore be given with cau- 
tion by the mouth, or perhaps, is better applied hypodermically. 
Abortion so seldom occurs after quinine that pregnancy is no objection 
to its administration. In general, it may be stated that quinine is often 
credited with many disadvantages which it does not possess, and that 
in cases of malaria, in which it is practically without a rival or substi- 



ACETANILIDE AND ANTIPYRINE SERIES. 373 

tute, only the most pronounced idiosyncrasy can justify withholding it. 
In other cases, as in septic fever, it may be a question whether it does 
not aggravate the condition when it is administered to very weak 
patients. 

BlBLIOGKAPHY. 

Binz. Arch. f. mikros. Anat., iii., p. 383. Virchow's Arch., xlvi., p. 67 ; li., p. 6. 
Experimentelle Untersuch. ueber das Wesen der Chininwirkung, Berlin, 1868. Arch, 
f. exp. Path. u. Pharm., i., p. 18 ; v., p. 39 ; vii., p. 275. 

Prior. Pfliiger's Arch., xxxiv., p. 237. 

Strassburg. Arch. f. exp. Path. u. Pharm., ii., p. 334. 

Eeubach. Ibid., v., p. 1. 

Eulenburg. Arch. f. Anat. u. Phys., 1865, p. 423. 

Jerusalimsky. Central, f. med. Wissen., 1876, p. 476. 

Horbaczewski. Monatshefte f. Chemie, xii., p. 221. 

Kerner. Pfliiger's Arch., ii., p. 200; iii., p. 93; vii., p. 122. 

Wild. Brit. Med. Journ., 1887, ii., p. 500. 

Cerna. Philadelp. Med. Times, x., p. 493. 

Kirchner. Berl. klin. Woch., 1881, p. 725. 

Liebermeister. Deutsch. Arch. f. klin. Med., iii., p. 23. 

Husemann. Therap. Monatsheft., 1888, p. 7. 

Appert. Virchow's Arch., lxxi., p. 364. 

Gottlieb. Arch. f. exp. Path. u. Pharm., xxvi., p. 419 ; xxviii., p. 167. 

Hertwig. Jena. Ztschr. f. Med. u. Naturwiss., xx., pp. 120 and 477. 

Merkel. Arch. f. exp. Path. u. Pharm., xlvii., p. 165. 

Santesson. Arch. f. exper. Path. u. Pharm., xxx., pp. 411 and 448 ; xxxii., p. 321. 
Skand. Arch. f. Physiologie, vii., p. 385. 

Lewizky. Virchow's Arch., xlvii., p. 352. 

Unruh. Ibid., xlviii., p. 227. 

Speck. Centralb. fur d. med. Wissen., 1876, p. 295. 

Bozck u. Bauer. Ztschr. f. Biol., x., p. 336. 

v. Noorden u. Zuntz. Arch. f. Anat. u. Phys., 1894, p. 203. 

Talma u. v. d, Weyde. Zts. f. klin. Med., ix., p. 276. 

Albertoni. Arch. f. exp. Path. u. Pharm., xv., p. 248. 

Schumacher. Arb. a. d. pharm. Inst, zu Dorpat, x., p. 1. 

See et Bochefontaine. Comptes rendus, xcvi., pp. 266 and 503 ; c, p. 644. 

Bochefontaine. Arch, de Phys., 1873, p. 389. 

Langlois et Varigny. Journ. de 1' Anat. et Phys., 1891, p. 273. 

Langlois. Arch, de Phys. [5], v., p. 377. 

Bossbaeh. Pharmakol. Untersuch., i., p. 145. 

Kumagawa. Virchow's Arch., cxiii., p. 134. 

Grethe. Deutsch. Arch. f. klin. Med., lvi., p. 189. 

Maragliano. Ztschr. f. klin. Med., xiv., p. 309; xvii., p. 291. 

Liepelt and Stuhlinger. Arch. f. exp. Path. u. Pharm., xliii., pp. 151, 168. 

Hedbom. Skandin. Arch. f. Physiol., ix., p. 33. 

Pohl. Arch. f. exp. Path. u. Pharm., xli., p. 111. 

Hare. Therapeutic Gaz., 1897, p. 433. 

De Schweinitz. Amer. Jour, of the Med. Scien., cxiv., p. 282. 

Cavazzani. Arch. Ital. de Biol., xxxii., p. 350. 

EUram. Arch, internat. de Pharmacodyn., ix., p. 289. ( Cinch onamine. ) 

Birch-Hirschfeld. Arch. f. Ophthalmol., Iii., p. 358. 

Word Holden. Arch, of Ophthal. and Otology, Nov., 1898. 

XXIV. THE ANTIPYRETICS. (ACETANILIDE AND 
ANTIPYRINE SERIES.) 

The antipyretics are a very recent addition to therapeutics, the old- 
est of this group now in use dating only from 1884. Up to 1875 the 
only means of combating high temperature were baths, vegetable alka- 
loids such as quinine and aconitine, or alcoholic preparations, but in 
that year Buss discovered that salicylic acid produced a fall in the fever 



374 ORGANIC DRUG^ ACTING AFTER ABSORPTION. 

temperature, and soon afterwards carbolic acid and resorcin and its 
isomers were introduced as antipyretics. In the meantime it had been 
shown that quinine is a quinoline derivative, and quinoline itself, as 
well as some of its simpler compounds, were found to have powerful 
antipyretic properties. Quinoline (C 9 H 7 N) was soon found to be 
dangerous from its producing collapse, but its derivatives Katrine 
(C 9 H 9 (OH)N - C 2 H 5 ), Kairoline (C 9 H g (CH 3 )(OH)NH) and Thalline 
(C 9 H 9 (OCH 3 )NH) were used extensively, although they have now been 
almost entirely abandoned. In fact the only quinoline bodies now 
used as antipyretics are Analgen and Thermifugine, which are still pre- 
scribed to a limited extent. 

A new antipyretic was introduced in 1884 under the name of Anti- 
pyrine, which is derived from phenylhydrazine by a series of reactions 
and has proved superior to all of the earlier drugs. Phenylhydrazine 
(C 6 H 5 — NH — NH 2 ) produces a fall in the fever temperature, but 
this is frequently accompanied by collapse and changes in the blood, 
which prevents its use in medicine. Several of the simpler compounds 
such as Pyrodine (acetylphenylhydrazine) and Antithermine (phenyl- 
hydrazine and laevulinic acid) have received a more or less extensive 
trial as antipyretics, but have proved dangerous and inferior to An- 

tipyrine, phenyl-dimethylpyrazolon, C 6 H 5 — N <pX 3 " " pW 3 ' 

The latter is still very largely used as an antipyretic, either in its orig- 
inal form or as a constituent of numerous combinations which have 
been introduced of late years. Among these may be mentioned Reso- 
pyrine (resorcin and antipyrine), Hypnal (chloral and antipyrine), 
Salipyrine (salicylic acid and antipyrine). 

Antipyrine early found a rival in Antifebrine or Acetanilide which 
was advised as an antipyretic in 1886 by Cahn and Hepp. Aniline 
(C 6 H 5 NH 2 ), from which it is derived, has also some action on the tem- 
perature, but like phenylhydrazine produces dangerous collapse and 
destruction of the blood cells. Acetanilide (C 6 H 5 NHCOCH 3 ), the 
first of its derivatives to be introduced, is not entirely devoid of this 
poisonous action, and has been supplanted to a considerable extent by 
more complex and less poisonous bodies. One of these, Exalgine 
(C 6 H 5 NCH 3 COCH 3 ), differs from antifebrine only in possessing a methyl 
group in the side chain, and seems to resemble it closely in its effects. 
Another which enjoyed a short trial is Benzanilide (C 6 H 5 OTIC 7 H 5 0) in 
which the acetyl radicle of antifebrine is replaced by benzoyl. It was 
soon found that both aniline and antifebrine underwent a partial oxida- 
tion in the body, with the formation of amidophenol or its derivatives, 
and the belief that the antipyretic effects were due not so much to the 
original substance as to these oxidation products led to the introduc- 
tion of numerous derivatives of paramidophenol (C 6 H 4 <,™ I. This 

body has antipyretic properties but suffers under the same disad- 
vantages as aniline. Among its derivatives the most satisfactory 
antipyretics are those in which the hydrogen of the hydroxyl is sub- 



AGETANILIDE AND ANTIPYRINE SERIES. 375 

stituted by an alkyl, while an acid radicle is added to the amido- 
radicle. The first of its compounds to be introduced was Phenacetine 

(C H 4 < nn w 3 ) which differs from antifebrine only in the addi- 
tion of ethoxyl in the para position. Methacetine, which resembles 
phenacetine in all points save in methoxyl being substituted for 
ethoxyl, appeared about the same time. Phenacetine was found to be 
much less dangerous than acetanilide and antipyrine, and has therefore 
been largely used, and has been followed by other bodies which are 
identical with it, except in the acid radicle attached to the nitrogen. 
Among these phenetidines may be mentioned Ladophenine (lactyl- 
phenetidine), Malahine (salicylphenetidine) and Saliphen and Salo- 
phen, which contain similar constituents, Apolysine and Citrophen 
(citryl-phenetidine), Kryofine (methylglycolic-phenetidine) and Pheno- 
cott (glycocoll-phenetidine), with its compound with salicylic acid, Salo- 
coll. 

Several urethane derivatives have also received a trial as anti- 
pyretics, among them being JEuphorlne (phenylurethane), which is 
somewhat poisonous, however, Thermodine (phenacetine-urethane) and 
Neurodine (acetoxyphenyl-urethane). 

With the exception of antipyrine and the quinoline compounds, all 
the antipyretics at present in use probably owe their activity to the 
formation of simple derivatives of paramidophenol in the tissues, 
and differ chiefly in the rapidity with which this decomposition occurs. 
A rapid formation of paramidophenol produces destructive blood 
changes and a tendency to collapse, while the antipyretic effects pass 
off very rapidly. Those drugs are found the most satisfactory anti- 
pyretics in which the decomposition proceeds gradually so that the 
temperature falls slowly and remains low for a longer time. The sim- 
pler antipyretics, such as antifebrine, have given way largely therefore 
to the phenetidine compounds. 1 Among these it is impossible to deter- 
mine the most suitable antipyretic. The question is a purely clinical 
one, and these drugs are thrown on the market in such profusion at 
the present time that clinical observers are unable to compare their 
effects satisfactorily, and in many cases seem satisfied to use one ex- 
clusively. Where the merits seem so equally divided, it is perhaps more 
important to learn to use one of them with judgment than to hurry 
after each new product without sufficient experience of its predecessor. 

Symptoms. — The most interesting effect of these drugs is the de- 
pression of the body temperature in fever, and in many other respects 
their action is not very definitely known at present. They are by no 
means very poisonous, normal animals showing no reaction to doses 
which are sufficient to cause marked changes in fever. In the frog, 
Antipyrine causes an increase in the reflex irritability, which sometimes 
leads to tetanic convulsions and is followed by depression, loss of the 
voluntary movements and eventually by complete paralysis and death. 

1 For a detailed discussion of these principles see V. Mering, Therap. Monatsh. 
1893, p. 577, and Hinsberg & Treupel, Arch. f. exp. Path. u. Pharm., xxxiii., p. 216. 



376 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

In mammals, its injection is followed at first by a period of quiet and 
sometimes of somnolence, which is said by some authors to occur also 
in the frog previous to the increase in the reflex irritability. Some 
rise in the reflex irritability may be made out in the mammal at this 
stage, and large doses cause convulsions and tremors, and subsequently 
unconsciousness and collapse, ending in complete paralysis. The pulse 
is accelerated by small doses, while in the later stages of poisoning it 
may be slow, and some dilatation of the skin vessels and flushing have 
been observed. The respiration is at first accelerated, and then be- 
comes slow and irregular when large doses are injected. In dogs, 
vomiting and dilatation of the pupil generally occur. 

Antifebrine is more poisonous than antipyrine in both frogs and 
mammals, but resembles it in its general effects, producing first a more 
or less marked stage of lessened activity, followed by convulsive move- 
ments. The respiration is not so much accelerated as by antipyrine, 
and, according to some observers, is slow from the beginning of the ac- 
tion. The heart is first accelerated and then slow and irregular, and 
cyanosis and collapse are more frequently observed than under anti- 
pyrine. Phenacetine and its allies are much less poisonous than the 
two foregoing, but in large quantities produce almost identical effects — 
somnolence followed by convulsions, cyanosis and collapse symptoms, 
first rapid, then slow respiration and heart. Analgen, which may be 
taken as a type of the quinoline derivatives, acts in a very similar way 
to the others, and is more toxic than phenacetine, and, according to 
some writers, than antipyrine. Some depression of the spontaneous 
movements and of the reflexes is described as following its adminis- 
tration to mammals, and large doses produce convulsions and cyanosis. 
Lactophenine is said to have a more sedative effect than the other an- 
tipyretics, and to induce complete narcosis in the rabbit. 

The Effects of the antipyretics in Man vary exceedingly, not only 
with the dose but with the individual patient. Many persons can take 
very large doses without apparent effect, while in others comparatively 
minute quantities produce symptoms of greater or less importance. The 
effects are not always the same even in one individual under the 
same dose of the antipyretic, and it is impossible to state at present 
what are the conditions that involve the peculiar train of symptoms. 
A very large number of disorders have been attributed to the anti- 
pyretics in man, but it is impossible to consider any here except those 
more commonly observed. Among these are shin eruptions of various 
forms, such as red, erythematous, itching patches or more widely dif- 
fused hyperemia resembling the onset of measles or scarlatina ; urti- 
caria occurs not uncommonly, while eczema and bullae are rarer. In 
some cases an cedematous swelling has been observed. Some fever 
occasionally accompanies the eruption and renders the diagnosis from 
the infectious exanthemata even more difficult. These skin affections 
seem to be elicited more frequently by antipyrine than by antifebrine 
and the phenetidine compounds. They have been attributed to dilata- 
tion of the cutaneous vessels, but this in itself is insufficient to explain 



ACETANILIDE AND ANTIPYRINE SERIES. 377 

their appearance, although it may be a favoring condition. Profuse 
perspiration not infrequently follows the use of the antipyretics in 
fever, and if the fall in temperature be rapid, and the action of the 
drug passes off soon, the subsequent rise of temperature may be accom- 
panied by shivering and rigor, but these symptoms are scarcely to be 
looked upon as direct effects of the drug, but rather as resulting from 
the rapid changes in temperature. They are produced much more 
frequently by the older and simpler antipyretics than by those of more 
recent introduction. 

Sometimes catarrh, burning and swelling of the throat and mouth are 
observed after antipyrine, and more rarely nausea and vomiting. Cerebral 
symptoms .are rarely elicited beyond slight dulness, confusion or apathy. 
Alterations of the hearing similar to those described under quinine 
have been observed in some cases. More serious symptoms are those 
of collapse, which are occasionally produced in susceptible persons, 
especially by large doses. Antifebrine is much more liable to elicit 
these than antipyrine, which in turn is more dangerous than phenacetine 
and the other phenetidine derivatives. In the milder cases of collapse 
the skin is cool, the pulse is rather small and rapid, and some anxiety 
and alarm is felt by the patient, but the condition passes off in a short 
time. In more severe cases the skin is cold and covered by a clammy 
perspiration, the heart is weak, irregular and sometimes fluttering, the 
temperature may be subnormal and jthe pupils are slightly dilated. 
The patient may be conscious, fainting may occur, or an apathetic, 
confused condition may be produced. The weakness of the heart is 
the chief source of anxiety, and the total failure of the circulation seems 
to be the cause of death. These cases of collapse occur more frequently 
when a rapid fall of temperature has been produced than under other 
circumstances, but may be observed in cases in which no fever has 
been present. 

Marked cyanosis occurs occasionally under all the antipyretics, but 
more frequently under antifebrine and the earlier members of the series 
than under antipyrine and the phenetidine compounds. Its cause is 
not satisfactorily explained as yet. According to some observers it 
is due to the formation of methaBmoglobin in the blood, but although 
this may often be a contributing factor, it is not the only cause, for 
cyanosis has been observed in cases in which no methsemoglobin was 
formed, and it is much more intense than that caused by the formation 
of the same amount of methremoglobin by other poisons. It is often 
accompanied by dyspnoea and acceleration of the pulse, and it lasts for 
a varying length of time, sometimes passing off in a few hours, at other 
times persisting for several days. 

Occasionally a certain tolerance is gained, and larger doses of the 
antipyretics are required to produce effect than were necessary at the 
beginning of the treatment. A few cases of chronic poisoning are 
recorded from the habitual use of these drugs in neuralgia. The symp- 
toms consisted in disturbance of the digestion, tremor, excitability and 
irritability, and disappeared when the drug was given up. 



378 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

Action. — The action of these drugs on the various organs is very 
imperfectly understood. They are generally supposed to have some 
depressant effect on the Nerve Centres, as is shown by the lessened 
movements and slight somnolence produced in man and animals. This 
effect is very slight in many cases, however, and it seems impossible 
to suppose that the action is in any way comparable to that of the true 
narcotics, for cerebral action may be induced by small doses which do 
not apparently influence the mental activity. Thus, neuralgic pain is 
often relieved by the antipyretics without causing somnolence or any 
appreciable depression, and it would therefore appear that if the ordi- 
nary doses influence the activity of the nerve cells, they must do so 
to a very slight extent, or perhaps their action may be confined to some 
special areas of the brain. Most of the antipyretics increase the ex- 
citability of the spinal cord at first, and this may lead to convulsions 
in the frog. The origin of the convulsions in mammals is still some- 
what doubtful ; in general, they seem to be of cerebral origin, but 
when large quantities are injected, they are seen even when the spinal 
cord is divided from the brain, so that the cord appears to be thrown 
into a condition resembling that discussed under strychnine poisoning. 
In considering the cause of these convulsions perhaps too little weight 
has been laid by some writers on the changes in the blood, respiration 
and circulation, for it is possible that the convulsions in some cases are 
asphyxial in character, and not due to the direct action of the poisons 
on the brain. In ordinary poisoning the peripheral Nerves and nerve 
ends do not seem to be seriously involved and the final paralysis in 
both frogs and animals is undoubtedly central. Santesson found 
that antipyrine tended to increase the power of the frog's Muscles, and 
several observers have noted that the nerves and motor terminations 
are paralyzed by the direct application of this drug. Antipyrine has 
some effect as a local anaesthetic when applied to the mucous membranes. 

The Heart in the frog and mammals is first accelerated and then 
slowed by the antipyretics in general, these alterations being entirely 
independent of the inhibitory mechanism and due to a direct effect on 
the cardiac muscle. The increased rhythm of the heart leads to a 
slight rise in the blood-pressure, which sinks again as the pulse becomes 
slower. There is no satisfactory proof that the vaso-motor centres are 
involved in the rise of pressure, although it is not unlikely that 
they undergo a primary stimulation at the same time as the respiratory 
centre. The vessels are said to be dilated by the perfusion of antipy^ 
rin'e solutions, but it seems improbable that this plays any role in or-, 
dinary methods of application. 

Most of this series except antipyrine and its compounds tend to 
cause alterations in the Red Blood Cells when they are given in large 
quantities. This action is manifested especially by the simpler bodies 
of the series, and is still more marked in poisoning from aniline, phenyl- 
hydrazine, paramidophenol or quinoline. On the other hand, most 
of the phenetidine compounds produce it much more rarely, and anti- 
pyrine seems devoid of this action. The alteration consists in the 



ACETANILIDE AND ANTIPYRINE SERIES. 379 

formation of methsemoglobin, which may be readily detected by its 
characteristic spectroscopic appearance. Small quantities of the anti- 
pyretics cause its formation within the blood-cells, which remain intact, 
but larger doses, especially of the more poisonous members, destroy the 
red blood cells and free the methsemoglobin in the plasma. In the 
blood various distorted, shrunken red cells may be observed, often en- 
tirely devoid of coloring matter, while part of the methsemoglobin seems 
to escape through the kidneys, and nephritis occurs in some cases with 
albumin, haemoglobin and even blood in the urine. This effect on the 
blood seems due to the decomposition of the antipyretics and the flood- 
ing of the tissues with paramidophenol, or the corresponding quinoline 
derivative. This decomposition proceeds more slowly in phenacetine 
and its allies and is absent after antipyrine, which explains the rarity of 
the symptoms after these drugs. When the antipyretics are added to 
blood outside the body no methsemoglobin is formed. Whether the 
simpler bodies, such as paramidophenol, are equally inert in the test- 
tube is unknown. 

All of the antipyretics have some Antiseptic action, which varies in 
the different members with their solubility and stability. Antipyrine 
is found to preserve blood from putrefaction for some days when added 
to it so as to form a solution of 2-5 per cent. Watery solutions 
of this strength destroy protozoa and stop the movements of the 
leucocytes, but antipyretics administered to the higher animals have 
no such effect on the emigration of the leucocytes from the vessels as is 
seen under quinine. 

The action of the antipyretics on the Metabolism of healthy men 
and animals has been the subject of a number of investigations which 
have given by no means uniform results, especially in regard to the 
nitrogen elimination. Antipyrine is said by Umbach, Hartmann, 
Engel, and Korner to lessen the urea and nitrogen excreted in health, 
but this diminution is comparatively small, and the exhaustive re- 
searches of Kumagawa failed to corroborate their statements, for he 
found with Coppola that antipyrine in either small or large quantities 
had no appreciable effect on the nitrogenous metabolism in health. 
The absorption of oxygen and the excretion of carbonic acid is un- 
changed by it, and a consideration of the whole of the evidence leads 
to the conclusion that antipyrine has either no influence or only an in- 
significant one on the metabolism of the healthy tissues. 

Antifebrine, on the other hand, has a distinct effect on the nitrogen 
eliminated, although this is only elicited by large doses. After ordinary 
quantities the urea and total nitrogen of the urine may be slightly aug- 
mented, but in large doses antifebrine causes an increase of 30-35 per 
cent, in these, which indicates a large increase in the tissue waste. 
Kumagawa found that after the administration of the drug had ceased, 
the organism economized its tissue waste, so that in the course of time 
the excessive metabolism during the antifebrine treatment was entirely 
compensated. The other antipyretics have not been examined so care- 
fully. Thalline is said by Kumagawa to increase the nitrogen elimi- 



380 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

nated like antifebrine, while some others have been said to lessen the 
metabolism in health, but these statements require confirmation. As 
regards the oxidation in the tissues as measured by the exchange of 
gases in the lungs, the antipyretics have not been shown to have any 
effect in healthy animals. 

The excretion of uric acid under the antipyretics has also been the 
subject of examination. According to Kumagawa, Tauszk and Yas 
it is increased by antipyrine, but Horbaczewsky found it diminished to 
some extent, while the number of leucocytes in the blood was increased. 
He considers it probable that both antipyrine and antifebrine increase 
the uric acid when given in large quantities, but Tauszk and Vas state 
that antifebrine has no effect on the uric acid excretion in health. The 
glycogen of the liver and muscle is increased by antipyrine according to 
a recent statement of Lepine and Porteret, and Iwanoff has described 
some obscure changes in the liver cells of the frog under antipyrine. 

The specific effects of the antipyretics on the Temperature, while rec- 
ognized by all, have been the subject of endless discussion, owing to 
the complex mechanism through which they are elicited. In the nor- 
mal animal the temperature is but little altered, except by doses large 
enough to produce collapse, but when it is abnormally high, as in fever, 
the antipyretics cause a fall of greater or less extent. This fall in tem- 
perature occurs at varying intervals after the ingestion of the drug, but, 
except in refractory cases, always begins within 2-3 hours. Its extent 
varies, the temperature sometimes reaching the normal or even a sub- 
normal point, while in others the change is insignificant. Continuous 
fever without any natural rise and fall is much less affected, as a 
general rule, than one with alternate rise and fall of the temperature, 
and in the latter form the result is much greater if the drug be given 
at the beginning of one of the natural remissions. 

The fall in temperature is often accompanied by flushing of the skin 
and perspiration. The oxygen absorbed and the carbonic acid excreted 
are lessened, and the urea and nitrogen of the urine are also dimin- 
ished after antipyrine, while they are not infrequently increased after 
antifebrine, especially when administered in large quantities. The 
heart is often reduced in rate, and the pulse improves in strength, but 
these changes are due to the fall in the temperature and not to the 
direct action of the drugs. Some remedies owe their antipyretic prop- 
erties to their increasing the secretion of the sweat glands, but although 
perspiration not infrequently occurs during the fall of temperature under 
the new antipyretics, this is merely a secondary result here, for when 
the perspiration is checked by atropine or agaricin, the fall of tempera- 
ture proceeds uninterruptedly. 

The temperature in healthy warm-blooded animals is kept uniform 
through a balance being established between the heat formation and its 
dissipation through the lungs, skin and other organs. If an excessive 
formation occurs, as during muscular exertion, this is counterbalanced 
by an increase in the output from the skin through the dilation of the 
vessels and by the perspiration. If, on the other hand, more heat is 



ACETANILIDE AND ANTIPYRINE SERIES. 381 

dissipated than usual through exposure to cold, the combustion of the 
tissues is increased and more heat is formed. The output of heat is 
thus determined by the degree of dilatation of the cutaneous vessels and 
the activity of the sweat glands, while the amount of heat formed varies 
with the voluntary and involuntary contractions of the muscles. In 
order to preserve a balance between these two factors, there must exist 
a coordinating mechanism, and this is supposed to be located in the 
basal ganglia of the cerebrum, in the region of the corpus striatum. 
Lesions in this neighborhood generally cause a very marked rise in the 
temperature, often without further disturbance, and it is of interest to 
learn that as long as the cerebrum is intact, shivering is produced by 
cold, while after the section of the peduncles the animal offers no 
resistance to a fall of temperature produced by cooling of the surface. 
Other facts might also be adduced to show that in the normal ani- 
mal the temperature is kept uniform by this coordinating mechanism, 
which controls both the output of heat through the skin and its for- 
mation by the contractions of the skeletal muscles. In many indi- 
viduals this coordination is not perfect in health, and in all it may be 
disorganized by poisons, such as those formed in fever. The more 
perfect the coordination, the smaller is the divergence from the normal 
temperature necessary to elicit a protective increase in the combustion 
or in the dissipation. The efficiency of the mechanism may therefore 
be measured by observing what fall of the body temperature occurs 
before shivering sets in, what rise produces dilation of the cutaneous 
vessels and perspiration. In this way it has been found that during 
fever the coordination is quite as perfect as in health, but that the pro- 
tective reactions are induced at a higher temperature. Thus, Richter 
found that a normal dog (temperature 38.6° C.) protected itself by 
shivering when its temperature was reduced by cold to 37.9°, while 
profuse perspiration broke out when its temperature was raised to 
39.1°. The same dog suffering from fever (temperature 40.4° C.) 
reacted by shivering when its temperature was reduced to 40.2° and 
by perspiration when it rose to 40.9°. The coordination is not de- 
stroyed or paralyzed by fever therefore, for it is in this case more 
sensitive to alterations of .the body temperature than in the normal 
animal. The same measures are taken to preserve a uniform temper- 
ature as in health, but the temperature maintained by these means is 
higher. If a comparison be made with the thermostat of the labora- 
tory, it may be said that in fever the mechanism is " set " for a higher 
temperature than in normal life, but that the apparatus acts efficiently 
for each temperature. This higher temperature is maintained by an 
increased metabolism or heat formation, and also in most cases by a 
lessened dissipation. The fever temperature itself seems to increase 
the metabolism, the tissues undergoing more rapid waste under it than 
in normal conditions. 1 

*It must not be supposed from the foregoing statements that fever consists only in 
an alteration of the normal temperature. This is only one of the symptoms produced 
by the poisons of fever, but is the only one affected by the antipyretics. 



382 



ORGANIC DRUGS ACTING AFTER ABSORPTION. 



The first explanation of the antipyretic action of this series was 
that they lessened the metabolism in the same way as quinine, and 
thus lessened the heat production. This view was suggested by the 
fact that some of them, such as kairine and thalline, are derivatives of 
quinoline, like quinine, and it was supported by the observation that the 
nitrogen eliminated and the oxygen absorbed were reduced in amount 
by their action in fever, and by a series of calorimetric experiments in 
which it appeared that the output of heat was lessened by their use. 
This explanation has of late years been abandoned by the great ma- 
jority of the investigators of the subject. The lessened tissue waste 
which is observed under the action of the antipyretics in fever is not 
due to their direct action on the tissues, but to the fall of temperature, 
the metabolism proceeding more slowly when the heat is reduced. 
If they acted on the tissues directly in fever, they would have a similar 
effect in health (cf. quinine), whereas antipyrine has no appreciable 
effect here, and antifebrine actually increases tissue waste. 

The earlier experiments in which the dissipation of heat was 
measured directly by the calorimeter indicated that it was lessened 

by the antipyretics, in fever, 
Fig. 35. while the results varied in 

health. Renewed investi- 
gations with more atten- 
tion to detail and with im- 
proved apparatus have shown, 
however, that the dissipation 
of heat in fever is much in- 
creased by the antipyretics, 
while in health they seem to 
have little effect. This aug- 
mentation in the output is 
due to dilatation of the cu- 
taneous vessels, which exposes 
a large amount of blood to 
the cold air. The dilatation 
is, great enough to be recorded 
by the plethysmograph in 
many cases, while in others 
flushing of the skin may be 
observed. The increased dis- 
sipation of heat is accom- 
panied by a lessened formation 
which, however, is much less 
important and which is gener- 
ally attributed to the metab- 
olism proceeding less actively 
at the lower temperature. In 
other words, the antipyretics reduce the temperature by increasing 
the output of heat, and the cells of the body grow and change 





s** 



Diagram to illustrate the relation between the warmth, 
output and the internal temperature. The unbroken 
line represents the changes in the warmth output, which 
is estimated at different times by measuring the height 
of this line from the abscissa AB. The broken line is 
that of the internal temperature. A to H normal ; &tH 
an injury of the brain caused a marked fall in the out- 
put and an increase in the internal temperature, which 
persisted until at P, antipyrine was administered. The 
internal temperature then fell rapidly while the output 
rose to beyond the normal. Contrast Fig. 33. (After 
one of Gottlieb's experiments.) 



ACETANILIDE AND ANTIPYBINE SERIES. 383 

less when removed from the hot-house temperature to which they 
have been exposed previously. It must be added, however, that some 
observers hold that the fall in heat formation is too great to be explained 
in this way, and suppose that the antipyretics lessen the combustion 
through some other action, but not by affecting the tissues directly. 

It has been stated already that the fevered animal resists any change 
in its temperature in the same way as the normal, and it might there- 
fore be expected that when the temperature is reduced by antipyretics 
the organism would at once increase its heat formation. The fact that 
this does not occur, but that, on the contrary, the metabolism is les- 
sened, indicates that some further change occurs, that the antipyretics 
do not only reduce the temperature by allowing the heat to escape, 
but also alter the condition of the coordinating mechanism by which 
the temperature is kept uniform. To return to the comparison with a 
thermostat, the body temperature is set at a lower point by the anti- 
pyretics, while it is set higher by the fever poisons. 

The action of the antipyretics on this coordinating centre is there- 
fore of interest, and has been examined both in health and disease. 
In healthy men the temperature does not undergo any marked change 
under the antipyretics for though it may fall a few tenths of a degree 
in some cases, this is of no significance. The sensitiveness of the coordi- 
nating centre is increased apparently, however, for in some individuals 
in whom hard muscular work causes a rise of temperature normally, 
this is absent or less marked after the antipyretics. In the same way 
the rise of temperature which occasionally is caused by very hot baths, 
is absent or diminished when antipyrine has been administered pre- 
viously. When the basal ganglia are cut off from their connections 
with the lower part of the body, neither septic injections nor antipy- 
retics have any eifect on the temperature, while after section above 
the basal ganglia, fever is caused, and the antipyretics induce the 
usual fall of temperature (Sawadowsky). In experiments in which a 
high fever was produced by lesions in the neighborhood of the ganglia, 
Gottlieb found that the antipyretics reduced the temperature and in- 
creased the output of heat to a marked extent, while the formation was 
increased to a less degree. 

Finally, the condition of the centre has been examined by Stern and 
Richter after the temperature had been reduced by antipyretics. 
They both found that the protective mechanism was called into play 
when the temperature was slightly raised, and generally when it was 
depressed. For example, a fevered dog (temperature 40.9° C.) re- 
ceived a dose of kairine, and its temperature was reduced to 37.6.° 
Attempts were now made to raise the temperature by external heat, but 
the animal resisted this by increasing the output as soon as the tem- 
perature rose to 37.8°. The coordination which maintained the tem- 
perature at 40.9° before the drug was administered now attempted to 
keep it at 37.6°. 

The results of these researches may be summed up shortly as fol- 
lows : The antipyretics reduce the temperature in fever through alter- 



384 



ORGANIC DRUGS ACTING AFTER ABSORPTION. 



ations effected in the heat-regulating nervous mechanism, which result in 
lowering the point at which the temperature is maintained. As a conse- 
quence of this action, a great increase in the dissipation of heat must 
occur in order to free the body from the warmth which it has accumu- 
lated, and this increased output 
is attained by dilatation of the 
cutaneous vessels. The seat of 
action of the antipyretics is 
probably situated in the base of 
the cerebrum. 

The precise nature of the 
changes wrought by the antipy- 
retics in the coordinating mech- 
anism is unknown. Gottlieb 
and Harnack suggest that it is 
depressed by them and this 
would accord with the widely 
held idea that fever temperature 
is due to some form of brain ir- 
ritation ; but their reasoning is 
open to objection, and specula- 
tion seems useless until more 
is learned regarding the normal 
function of this organ. 

When the temperature is de- 
pressed too rapidly by these 
remedies, a condition of collapse 
is often produced, while in other 
cases the loss of heat caused by 
the dilatation of the skin vessels seems to be excessive, and shivering 
and rigor follow in order to increase the production. 

When the temperature has reached the new point fixed by the coor- 
dination under the influence of the antipyretic, the heat dissipation 
rapidly diminishes and may become less than normal, because the new 
temperature is maintained at a constant point by the same mechanism 
as the normal. 

The antipyretics are rapidly absorbed, and as rapidly Excreted by 
the kidneys, so that they disappear from the body within 24-30 hours 
after their administration. 







Fig. 


36. 

• 




c 










41 






40 










39 






38 




^ 






37 
30 
35- 


- 


f \ 

i \ 


\ 
\ 




34 


- \ 
\ 




\ 




33 


\ 




\ 




32 


' N 


1 


^ 




31 


" 




\ 


^ 



p 1 



4 B 



Curve of the internal temperature (unbroken 
line) and of the skin temperature (dotted line) in 
fever treated with antipyrine (Rosenthal). The ab- 
scissa AB represents the time in hours, the vertical, 
AC, the temperature Centigrade. At P antipyrine 
was given, and the skin temperature rose at once 
(augmented heat output). The internal tempera- 
ture soon began to fall, and after it had reached a 
certain point, the skin temperature fell again as the 
capillaries contracted. 



The fate of antipyrine seems to differ in different animals. In the dog it 
is found to be" partially oxidized to oxyantipyrine which is excreted in the 
urine in combination with glycuronic and sulphuric acids. In others it is 
said to be excreted in the urine unchanged. Antifebrine undergoes a partial 
oxidation, the final product differing in different animals, but none of the 
original body appears in the urine except after very large doses. In man it 

C 6 H 4 < 2 3 J and as paramidophenol 

or another of its compounds, both being in combination with sulphuric and 
glycuronic acids. In the rabbit's urine paramidophenol alone is found, while 



ACETANILIDE AND ANTIPYR1NE SERIES. 385 

in the dog this is accompanied by oxycarbanil (C 6 H i < > CO) ; in each 

case it forms a double sulphate or glycuronate. The fate of the other anti- 
pyretics resembles that of antifebrine, the quinoline derivatives undergoing a 
partial oxidation resulting in a body analogous to paramidophenol, while the 
phenetidine compounds are partially decomposed and appear in the urine as 
glycuronates of phenetidine. The combinations containing salicylic acid 
break up in the body, and the acid appears in the urine as salicyluric acid, 
while the rest of the molecule undergoes the usual partial oxidation. 

The presence in the urine of these bodies, or rather of further pro- 
ducts of their oxidation, gives it a dark reddish-brown color, which may 
be observed when it is passed, or more frequently after it has been ex- 
posed to the air for some time. 

Preparations. 

Acetaniltdum (IT. S. P., B. P.), acetanilide or antifebrine. 

Acetanilide is a colorless, crystalline body insoluble in water, soluble in 
alcohol, ether and chloroform. It has no odor when pure, but has a slight 
burning taste. It may be prescribed in powder, suspended in mucilage, or 
in cachets or lozenges. The B. P. gives as the dose 0.006-0.2 G. (1-3 grs.), 
but is often given in larger doses, up to 0.6 G. (10 grs.). 

Phenazoxtjm (B. P.), phenazone, or antipyrine, forms colorless inodorous 
ervstals, with a bitter taste, very soluble in water, alcohol and chloroform. 
0.3-1.3 G. (5-20 grs). 

Phenacetenum (B. P.), colorless, tasteless crystals, insoluble in water, 
0.3-1 G. (5-15 grs.), in the same forms as acetanilide. 

Non-official. 

Thalline is generally seen as thalline sulphate, a colorless crystalline sub- 
stance, of a weak aromatic odor and slightly bitter taste, soluble in 7 parts 
of water. 0.2-0.5 G. (3-8 grs.). 

Exalgine resembles acetanilide except in its greater solubility in water, 
and may be given in the same quantity. 

Malakine, Lactophenine, Thermodine, Neurodine, Saliphen and Salophen all 
resemble each other in being insoluble in water, colorless and crystalline, 
and are prescribed in the same way as acetanilide and in doses of 0.5-1 G. 

Phenocoll is generally used as the hydrochlorate, which is fairly soluble in 
water, while Salocoll is insoluble. 0.5-1 G. (8-15 grs.). 

Malakine, Saliphen, Salocoll and Salophen all break up in the body, freeing 
salicylic acid, so that, in addition to the antipyretic action, the characteristic 
effects of this acid may be elicited by them. 

The antipyretics are almost invariably given by the mouth. Antipyrine 
has been injected hypodermic-ally, but is somewhat painful, because much 
larger quantities have to be used than are generally given by this method, 
and the solutions have, therefore, to be more concentrated (30-50 per cent.). 

Therapeutic Uses. — The antipyretics are used chiefly to Reduce the 
Fever Temperature. The most satisfactory results are obtained from 
those which act somewhat slowly, but which preserve a low temperature 
for some time, and antipyrine and the phenetidine compounds are thus 
preferable to the earlier remedies, which produce a more abrupt fall, after 
which the temperature soon regains its former height. The best effects 
are obtained when the antipyretic is given at the commencement of a 
natural remission, the temperature often falling 2-4 degrees in the course 
of the next 2—3 hours, and only rising slowly afterwards. In some 
25 



386 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

fevers the antipyretics have much less tendency to lower the tempera! 
ture than in others. Thus in septicaemia larger doses are required than 
in typhoid and not infrequently no satisfactory reduction of the tempera- 
ture follows the administration of the maximal quantity. Pneumonia 
is also said by some writers not to be affected so easily as some other 
febrile conditions in which the heat-regulating centre appears to be in 
a less stable condition, as is manifested by the occurrence of large spon- 
taneous variations of temperature. The reduction of the temperature 
by the antipyretics lasts only as long as the drug is present in sufficient 
quantity in the body, and accordingly as soon as sufficient has been 
excreted, the intoxication of the regulating mechanism begins again, and 
the temperature soon rises to its former height. The antipyretics do not 
act on the cause of the disease, but only remove one of the symptoms, 
but this in itself is not an argument against their use, as is apparently 
believed by some writers, because as long as the physician is unable 
to treat the cause directly, he is justified in taking such measures as 
are possible to remove the symptoms, rather than in adopting an ex- 
pectant treatment, pure and simple. The extensive use of these reme- 
dies shows very clearly that the high temperature is merely a symp- 
tom of disease, and not the disease itself, and the question has been 
much debated as to whether the reduction of fever is in any way bene- 
ficial. No one questions that some antipyretic measures should be 
taken when the temperature rises so high as to form a danger in itself, 
but their use in ordinary fever cases is more doubtful. In the early 
days of treatment with these remedies, von Jaksch asserted that the 
antipyretics, far from aiding the patient in fever, prolonged and re- 
tarded convalescence, but this does not seem to be correct for the less 
violent modern ones. It has recently been shown by Schutze that the 
use of the antipyretics does not retard the formation of the protective 
substances (antitoxins) to which the recovery from fever is attributed, 
for in infected animals treated with enormous quantities of antipyrine 
the serum displayed the same agglutinating properties towards the 
bacilli as that of controls which were not subjected to any medication. 
A more serious argument against their use in fever is that the course 
of the disease is less readily followed, because one of the guiding symp- 
toms — the temperature variations — is no longer dependent solely 
upon the severity of the intoxication with the fever poisons, and both 
diagnosis and prognosis are thus rendered more difficult. For example, 
in typhoid fever a sudden fall of temperature often gives the first in- 
dication of such a complication as haemorrhage, but if an antipyretic 
has been given beforehand, this indication may be entirely absent. On 
the other hand, it is urged in favor of the antipyretic treatment that 
the patient feels more comfortable and easier when the temperature is 
reduced, and that this alone may favorably influence the course of the 
disease. Besides, the high temperature in itself increases the tissue 
waste, and causes larger draughts on the resources of the patient than 
would be made with the same amount of poison in the tissues at a 
lower temperature ; and although the influence of the high temperature 



ACETANILIDE AND ANTIPYRINE SERIES. 387 

on the metabolism was undoubtedly exaggerated at one time, this con- 
sideration is by no means devoid of weight. The theory that fever is 
a defensive measure taken by the organism against the causes of dis- 
ease and ought not to be interfered with therefore, is now seldom men- 
tioned. The antipyretic treatment of fever is of value, then, in cases 
where the temperature is so high as to endanger life, in cases in which 
the rise of temperature is the chief cause of distress and no complica- 
tions are to be apprehended, and, in general, in cases in which the 
increased comfort of the patient produced by them is not counterbal- 
anced by their obscuring the diagnosis and prognosis. On the other 
hand, there is no reason to suppose that it shortens the course of most 
fevers, or that it prevents complications of any kind, except excessively 
high temperature, and the routine treatment of fever with antipyretics 
is to be deprecated. 

The chief rival of the antipyretics in the treatment of fever in the 
present day is the so-called cold-bath treatment, in which the fever 
patient is bathed frequently in water the temperature of which varies 
from 70-90° F. in different hospitals. The temperature generally 
falls to a considerable extent under this treatment, and very often a 
general improvement in the symptoms occurs.. The effect on the tem- 
perature is mainly due to the abstraction of heat from the body, and 
thus far corresponds to that of the antipyretics. In the cold-bath treat- 
ment, however, the loss of heat is not immediately due to the dilata- 
tion of the skin vessels, for it may be questioned whether even water 
at 90° F. is sufficient to produce this, and baths at 70° F. have rather 
the effect of constricting the vessels primarily, whatever may be the 
subsequent effect. The heat output increases here from the change in 
the external medium, and not from any alteration in the skin itself. 
The fall of temperature is generally not so great as under the anti- 
pyretics, and the regulation is not directly affected, for the patient 
shivers and becomes cyanotic long before the normal temperature is 
reached. The therapeutic virtue of the cold bath was formerly believed 
to lie exclusively in the abstraction of heat and the fall of temperature, 
but many advocates of the treatment now hold that this is of less im- 
portance than the effects on the circulation and the brain, which are 
elicited reflexly by the cold water applied to the skin, and which are 
not now believed to be due to the fall in temperature. Whether this 
view is correct or not, the whole nature of the fall in temperature is 
different from that produced by the antipyretics, and the metabolism, 
instead of becoming less active as it does under the latter, rather tends 
to increase under the cold baths, at least as far as the tissue change can 
be measured by the nitrogen excreted. The relative therapeutic value 
of the two methods of treating fevers can only be determined by clin- 
ical experiment, and the present attitude of the clinicians, which tends 
to favor the cold-bath treatment, may be reversed in course of time. 
However the matter may stand in hospital practice, in which trained 
assistance is available, the antipyretics have a great advantage in many 
cases in which treatment has to be carried out without any such facili- 



388 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

ties, for the administration of these drugs may, of course, be entrusted 
to ordinary persons, whereas the cold bath can be given only by 
the physician himself or by trained attendants. Particularly in the 
milder fevers, where no complicated measures, such as the cold bath, 
are considered necessary, the antipyretics give relief to the patient by 
removing the feeling of heat and discomfort. 

Other antipyretic drugs are quinine, aconite, digitalis, and alcohol, 
but none of these produce an equal fall of temperature unless with the 
presence of alarming and dangerous symptoms. Aconite and digitalis 
are generally supposed to reduce the temperature through their effects 
on the circulation, although it is not impossible that they may also 
affect the centres for heat regulation. Quinine acts probably through 
reducing the metabolism, and alcohol by dilating the skin capillaries, 
and perhaps by lessening the movements and thereby the formation 
of heat. All of these drugs are used very much less as antipyretics 
now than formerly, as, besides their undesirable secondary effects, the 
fall of temperature is less certain and less profound than under the 
modern antipyretics. 

The antipyretics are also used very largely to relieve Neuralgic Pain 
and Headache, often with complete success. So little is known re- 
garding the pathology of these diseases that it would seem premature 
to discuss the method in which these remedies act. By many they are 
supposed to have a sedative or depressant effect on the central nervous 
system, but this must be limited in its range, for quantities sufficient 
to remove pain often leave the mind perfectly clear. The analgesic 
action of these bodies is apparently quite different from that of mor- 
phine, for in many instances in which the latter is successful they fail 
to alleviate the condition. On the other hand antipyrine and its allies 
can often be used where morphine is contraindicated, either from the 
danger of the habit being formed, or from the somnolence it induces. 
The antipyretics appear to be of little or no value in relieving the 
pain caused by acute inflammatory conditions, while on the other hand 
they are almost specific in some neuralgic cases. Almost all of the 
antipyretics are efficient in these cases, but larger doses are generally 
required than to reduce fever, and the more powerful, such as antifebrine, 
are often preferred to the safer and more slowly acting phenetidines. 

Several of the antipyretics have been used as Substitutes for Quinine 
in the treatment of malaria, but none of them seem to have the specific 
action of the latter on the organism of malaria, and, although they may 
reduce the temperature, they do not prevent the other symptoms and 
do not remove the cause of the disease. In the same way they do not 
seem to equal salicylic acid in efficiency in acute rheumatism, although 
here again they reduce the temperature. This does not apply, of 
course, to those of the antipyretics, such as malakine, which form 
salicylic acid in their decomposition in the body. It is to be noted 
that the amount of salicylic acid thus formed from the ordinary dose 
of the antipyretics, is considerably smaller than would be given if the 
acid itself were prescribed. 



ACETANILIDE AND ANTIPYBINE SERIES. 389 

The antipyretics are used to a considerable extent in cases of dia- 
betes insipidus and mellitus and appear to relieve the discomfort and 
in some cases to improve the general condition. In whooping cough 
antipyrine often lessens the severity of the attacks and also renders 
them less frequent, and is said to shorten the course of the disease. 

The use of antipyrine and other members of this series as sedatives in 
hyperactivity of the motor functions of the brain, such as epilepsy aud 
chorea, has not been attended with great success, although temporary im- 
provement has occasionally been noted as after so many other remedies. 

Antipyrine and several others of this series have been advocated as local 
sedatives or anaesthetics, and have been used occasionally to lessen the 
irritability of the throat and larynx and thus to permit of the minor manipu- 
lations of laryngology. Holocaine, a body closely related to phenacetine, 
has been employed to a limited extent as a local anaesthetic in ophthalmol- 
ogy, but appears to be more poisonous than other equally efficacious drugs, 
such as eucaine. 

Thalline has been advised as a urethral injection in gonorrhoea. 

The occurrence of collapse and other symptoms has led to a consid- 
erable amount of distrust of the antipyretics among many of the med- 
ical profession. In justice it has to be remembered that in many cases 
these symptoms were produced only by very large doses, and that 
since experience has shown that beneficial results may be obtained by 
smaller quantities, these cases have notably diminished in medical 
practice. Unfortunately, this distrust is not entertained by a large 
class of the laity, and numerous cases of poisoning arise from the im- 
pression that the antipyretics are not dangerous drugs. For the most 
part, poisoning seems to be due to a peculiar sensitiveness or idiosyn- 
crasy, which cannot be foreseen, but in cases of great exhaustion and 
asthenia, especially when accompanied with anaemia, these drugs have 
to be used with great care or avoided entirely. 

Bibliography. 

Umbach. Arch. f. exp. Path. u. Pharm., xxi., p. 161. 

Biess. Ibid., xxii., p. 127. 

Sawadowsky. Centralbl. f. med. Wiss./ 1888, p. 145. 

Martin. Therap. Gazette, xi., 1887, p. 289. 

Lepine u. Porteret. Comptes rendus, cvi., p. 1023, and cvii., p. 416. 

Jaffe u. Hilbert. Ztschr. f. physiol. Chem., xii., p. 295. 

Morner. Ibid., xiii., p. 12. 

Gressly. Inaug. Diss., Bern, 1891. 

Nencki. Arch. f. exp. Path. u. Pharm., xxx., p. 306. 

v. Mering. Therap. Monats., 1893, p. 577. 

Hinsberg u. Treupel. Arch. f. exp. Path. u. Pharm., xxxiii., p. 216. 

Treupel. Deutsch. med. Woch., 1895, p. 222. 

Pellacani. Arch. Italien. de Biologie, viii., p. 76. 

Lepine. Kevue de Medicine, 1887, p. 306. 

Cahn u. Hepp. Berl. klin. Woch., 1887, p. 4. 

Henrijean. Maly's Jahresber. u. Thierchemie, xvii., p. 351. 

Filehne, Liebermeister, etc. Congress f. inn. Med., 1885, pp. 118-185 ; 1896, pp. 3-100.. 

Mliller. Deutsch. med. Woch., 1887, p. 27. 

Kumagawa. Virchow's Arch., cxiii., p. 134. 

Tauszku. Vas. Ungar. Arch. f. Med., i., p. 204. 

Hinsberg u. Kast. Cent. f. d. med. Wiss., 1887, p. 145. (Phenacetine.) 

3faass. Zts. f. klin. Med., xxviii., p. 139. (Analgen. ) 



390 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

Filehne. Eerl. klin. Woch., 1882, p. 681 ; 1883, p. 77. 

Stern. Zts. f. klin. Med., xx., p. 82. 

Hildebrandt. Virchow's Arch., cxxi., p. 1. 

Richter. Ibid., cxxiii., p. 118. 

C. Rosenthal, Arch. f. Anat. u. Phys., 1888, p. 1. 

W. Rosenthal. Ibid., 1893, Suppl., p. 243. 

Simon and Hock. Johns Hopkins Hospital Bulletin, 1890. 

Maragliano. Ztschr. f. klin. Med., xvii., p. 291, and xiv., p. 309. 

Evans. Therap. Gaz., 1887, pp. 237 and 379. 

Gottlieb. Arch. f. exp. Path., xxvi., p. 419, and xxviii., p. 167. 

Kraus. Wien. klin. Woch., 1894, pp. 229 and 275. 

Harnack. Therap. Monats., 1894, p. 101. 

Horbaczewski. Monats. f. Chem., xii., p. 221. 

Fraenkel. Zts. f. klin. Med., xvii., Suppl., p. 239. (Pyrodine. ) 

Riedel. Zts. f. Heilkunde, xvi., p. 55. 

Penzoldt. Arch. f. exp. Path. u. Pharm., xxvi., p. 313. 

Lispelt u. Stuhlinger. Ibid., xliii., pp. 151, 168. 

Tappeiner. Ibid., xxviii., p. 295, and xxx., p. 231. 

Heinz. Virchow's Arch., cxxii., p. 112. 

Schutze. Zeitschr. f. Hygiene, xxxviii., p. 205. 

Lawrow. Zeitschr. f. phys. Chernie, xxxii., p. 111. 

Riethus. Arch. f. exp. Path. u. Pharm., xliv., p. 239. 



XXV. ANTISEPTICS OF THE AROMATIC SERIES (CAR- 
BOLIC AND SALICYLIC ACID SERIES). 

Various balsams and wood-tar and some of its derivatives have long 
enjoyed a certain reputation in surgery, but the true value of the 
bodies of the aromatic series has only been realized since the systematic 
treatment of wounds with antiseptics was introduced by Lister some 
thirty years ago. The first antiseptic proposed by him was carbolic 
acid, and this held its position for several years, when it was discovered 
that bodies of similar origin, and others of entirely different composi- 
tion possessed equally great advantages as antiseptics with less liability 
to induce poisoning. Of late years a very large number of antiseptics 
belonging to the aromatic chemical series have been introduced, and 
have been discarded, often, it would appear, without sufficient exami- 
nation. It is not within the scope of such a work as this to examine 
all of these, especially as the effects of many of them differ only in 
detail, but the chief, active principles will be mentioned. 

The great mass of the aromatic antiseptics are obtained from coal- 
or wood-tar by more or less complicated reactions, and are often known 
as the coal-tar or tar antiseptics. 

The hydrocarbons benzene or benzol, toluol, xylol are too volatile for use as 
antiseptics, and the only hydrocarbon used for this purpose is Naphtalin(C 10 H 8 ). 

Among the hydroxyl compounds of benzol, Carbolic Acid or Phenol 
(C 6 H 5 OH) is the best known. The dioxybenzols (C 6 H 4 (OH) 2 ), three in num- 
ber, hydroquinone, pyrocatechin, and resorcin have also been used in medicine, 
and resorcin was at one time a popular antiseptic, although it has latterly 
fallen into disuse. 

Among the trioxybenzols, Pyrogallol (C 6 H 3 (OH) 3 ) alone has been used 
extensively as an antiseptic in skin diseases, and is still considered of value 
in certain conditions. 

Hydroxyl derivatives of other hydrocarbons are the two Naphtols, a- and 
/3-, (C 10 H 7 OH) which are used as intestinal disinfectants. Thymol (C 6 H 3 (CH 3 )- 



ANTISEPTICS OF THE AROMATIC SERIES. 391 

(C 3 H 7 )0H), obtained from thyme, was introduced as a substitute for carbolic 
acid, but has fallen into disuse. More recently the cresols, C 6 H 4 (OH)(CH 3 ), 
of which three are known, have attained some prominence as antiseptics. 

The phenol ethers, anisol and phenetol (C 6 H 5 OCH 3 and C 6 H 5 OC 2 H 5 ) have 
never been introduced into therapeutic use, but guaiacol (C 6 H 4 (OH)(OCH 3 )), 
the methyl ether of pyrocatechin, has had some use of late years as an 
antiseptic and antipyretic. A combination of guaiacol and carbonic acid 
known as guaiacol carbonate (CO(OC 6 H 4 OCH 3 ) 2 ) has also been used. Other 
dioxy-derivatives are the creosols (C 6 H 3 (CH 3 )(OH)(OCH 3 )), which are im- 
portant constituents of wood-tar and of creosote. 

The substitution of chlorine for hydrogen in the benzol ring seems to in- 
crease its antiseptic power, and monochlorophenol (C 6 H 4 C10H) and trichlor- 
phenol (C 6 H 2 Cl 3 OH) have been suggested as antiseptics. A similar intensified 
action is obtained by the substitution of chlorine in the members of the 
methane narcotics. (See page 129.) 

The presence of the carboxyl group ( — COOH) lessens the poisonous action 
of the aromatic series exactly as in the case of the methane series. Several 
acids have been suggested as internal antiseptics, therefore, and one of them, 
Salicylic acid (C 6 H 4 OHCOOH), is perhaps the most important of all the benzol 
compounds at the present time. Benzoic acid (C 6 ELCOOH) is an equally 
powerful antiseptic, but is comparatively seldom used as such. It is the 
chief constituent of several of the " balsams," in which it is often accom- 
panied by cinnamic acid (C 6 H 5 CH=CHCOOH). 

Salicylic acid is the only one of three isomeric acids that has been found of 
value. It is used either as the pure acid or more frequently as the Salicylate 
of Sodium, or in the form of an ester. One of these, methylsalicylate, has long 
been known as the oil of wintergreen and as sweet oil of birch. Another well- 
known ester is the phenyl salicylate or Salol, (C 6 H 4 OHCOOC 6 H.), while 
others of less widespread reputation are cresalol (salicylate of cresol), betol 
(salicylate of /3-uaphthol), salithymol (salicylate of thymol). Several other 
salicylic compounds are used as antipyretics as well as for their action as 
salicylates and are mentioned among the antipyrine series. (Page 374.) 
The most recent substitute for salicylic acid is aspirin or acetylsalicylic acid 
(C 6 H 4 OC 2 H 3 O.COOH). 

Another acid which has been used as a substitute for salicylic acid is 
cresotinic acid (C 6 H 3 (CH 3 )(OH)(COOH)), and the oxynaphtoic acids (C 10 H 6 (OH)- 
(COOH)) have been suggested as antiseptics. 

Instead of carboxyl, the sulphon radicle has been attached to phenol in 
order to lessen its toxicity, and in this way the so-called sulphocarbolates 
were formed. They must be distinguished from the ether-sulphuric acids 
or double sulphates in which the — HS0 3 is attached to the carbon of the 
ring by oxygen, while in the sulphocarbolates the connection between the 

ATT 

sulphur and the carbon is direct. (Sulphocarbolate of sodium, C 6 H 4 < G;n ^ 
sodium-phenol double sulphate, C 6 H 5 OS0 3 Na.) : bU 3 JNa ? 

When two hydrogen atoms of the benzol molecule are substituted by 
other elements or radicles, three different chemical products may result, 
and these are known as ortho-, meta- or para-compounds, according to the 
relation the two substituted atoms bear to each other. These three isomeric 
forms very often differ in toxicity and also in their antiseptic power, but no 
general statement can be made as to their relative position, for the ortho- 
compound is sometimes the most powerful antiseptic, as in salicylic acid ; 
in others the meta-compound, as in metacresol, while parachlorphenol is 
more strongly antiseptic than either ortho- or metachlorphenol. 

Many crude preparations of these bodies are still in use and have the ad- 
vantage of cheapness over the pure principles, and are therefore preferred 
where disinfection has to be carried out on a large scale. 

Wood-tar varies in its composition with the wood from which it is ob- 
tained. The most important constituents are generally guaiacols and creo- 



392 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

sols and their homologues, while carbolic acid and the cresols are less 
largely represented. Along with other only partially known substances, 
some hydrocarbons and acids such as acetic acid, also occur. 

Creosote is obtained from beech tar and consists chiefly of guaiacol and 
creosols with very little carbolic acid or cresol, which latter have a lower 
boiling point and are removed in the course of preparation. 

The volatile or ethereal oils have also antiseptic properties, and, in fact, no 
line of demarcation can be drawn between the volatile oil series and the 
antiseptics proper, for many bodies occur in both groups, and the great 
majority of the constituents of the volatile oil series belongs to the benzol 
compounds. The earliest antiseptics known were those occurring in plants, 
as is shown by the use of various herbs in embalming in Egypt. In later 
times several of the balsams, which contain benzoic and cinnamic acids dis- 
solved in volatile oils, were credited with beneficial effects in the treatment 
of wounds. 

Ichthyol is the ammonia salt of a sul phonic acid derived from the tar of a 
bituminous shale which is found in the Tyrol, and which contains the re- 
mains of many fossil fishes. The constitution of ichthyol is still doubtful and 
it is even undecided whether it is not really a mixture of a number of bodies. 
It contains a high percentage of sulphur, which seems to be only in part in 
the form of sulphons, in part in tha of mercaptans and sulphides. Thiol is 
an artificial product formed as a substitute for ichthyol by the action of sul- 
phur and afterwards of sulphuric acid on the tar obtained from brown coal. 
It seems to consist chiefly of sulphons, and is very soluble in water. Tumenol 
is another artificial substitute for ichthyol. Naphtalan is prepared from raw 
naphtha by distillation and is used instead of ichthyol. 

Action. — The simpler bodies of the aromatic series produce symptoms 
in the living organism which present great similarity in their general 
features, although they differ in details. As a general rule it is found 
that the simpler members of the series are much more poisonous to the 
higher animals than the more complex ones, while the latter are equally 
or more efficient as poisons in the lowest living forms. They are all 
possessed of a more or less marked action on the central nervous sys- 
tem which is entirely different from that of the methane narcotics 
however. The brain and spinal cord are thrown into a condition of 
abnormal irritability, which is betrayed by an increase in the reflex 
movements, and tremor and convulsions, and which is not due to the 
removal of inhibition as in the case of the methane compounds. Later, 
a stage of prostration and collapse is developed, which may simulate that 
seen in the narcosis of the fatty series, but does not seem to be identi- 
cal with it, for though in man the consciousness is often lost in this 
stage, the collapse in animals is in many cases not accompanied by loss 
of sensation or of the voluntary movements. The symptoms are gen- 
erally those of great muscular weakness and indicate depression of the 
vital centres of the medulla oblongata and of the heart rather than 
complete loss of the cerebral functions. They resemble surgical shock 
more than the anaesthesia following the use of chloroform and ether, 
and are probably of a different nature from the latter. 

Many of the members of the benzol series tend to destroy the red 
cells of the blood and to form methaBmoglobin ; this effect is especially 
developed in the case of pyrogallol and will be described under it in 
detail. Most of these antiseptics reduce the temperature in fever, 



ANTISEPTICS OF THE AROMATIC SERIES. 393 

while they have little effect on that of the normal body unless when 
given in large enough quantities to produce collapse. The cause of 
the fall of temperature in fever under the action of these drugs is not 
satisfactorily explained, although it seems probable that the process is 
the same as in the antipyrine series, with which they are nearly allied. 
The aromatic poisons differ from the typical members of the methane 
series in their effects on protoplasm in general. Alcohol and ether 
destroy life in all forms of protoplasm when they are brought in con- 
tact with it in sufficient concentration, but the phenols and acids of 
the aromatic series do so in more dilute solutions, and in fact owe 
their importance in medicine to their activity as general protoplasm 
poisons. 

Small quantities of the aromatic bodies seem to increase the activity of 
living matter, at any rate under some conditions, for the alcoholic fermen- 
tation is said to be accelerated by the presence of minute proportions of these 
poisons, and in the higher animals some of them increase the nitrogenous 
metabolism, while larger doses destroy the yeasts and also the tissues of the 
body. The evidence of central nervous irritation might also be cited in 
support of the view that the members of the aromatic series first accelerate 
and then retard protoplasmic activity, but the evidence is too limited as yet 
to admit of such a generalization. 

Therapeutic Uses. — The members of the aromatic series are used in 
therapeutics chiefly as disinfectants and antiseptics, that is, to destroy 
or retard the growth of pathogenic and putrefactive microorganisms 
and yeasts. Their introduction by Lister to prevent the infection of 
wounded surfaces in surgery was followed by a revolution in surgical 
methods, which can only be paralleled by that which followed the in- 
troduction of anaesthetics some twenty years earlier. 

The successful treatment of local infections by means of antiseptics 
encouraged the hope that general septic diseases might be as favorably 
influenced by them, but the two conditions are obviously entirely dif- 
ferent, for in the case of a local infection the remedy may be applied 
at the diseased point, and, although it may destroy the life of the 
superficial cells in the neighborhood, this is not of vital importance. 
On the other hand, a disinfectant, acting throughout the tissues of the 
body in sufficient quantity to destroy the microbes of infection, must 
have an equally unfavorable effect on the cells of the host, unless it 
has a specific action on the parasite, and this is very exceptional. 

A disinfectant in the strict use of the term is a substance used to 
destroy microbes, while an antiseptic, while not actually killing the 
germs, prevents their growth as long as it remains in contact with them. 
A disinfectant is accordingly only intended to act for a short time, for if 
the infected matter be once rendered sterile it can only become dan- 
gerous by being again contaminated. For example, a room requires 
only to be disinfected after a case of infectious disease. A wound, on 
the other hand, even though completely disinfected may become con- 
taminated again very easily and an antiseptic maybe required to prevent 
the further growth of microbes. Many substances are disinfectant in 



394 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

large quantities and antiseptic in more dilute solutions, but others are 
too weak to disinfect thoroughly though they retard the growth of 
pathogenic organisms, and still others may be employed to disinfect 
but are unsuitable for use as antiseptics, either because they are too 
poisonous to be applied for a sufficient time or because they lose their 
effects on the microbes (peroxide of hydrogen group). 

The uses of the antiseptics and disinfectants may be stated as follows : 

1. To Disinfect Rooms, Furniture, Clothes, etc. — For these purposes, 
the strongest and cheapest drugs which do not actually injure the 
objects may be employed. None of the aromatic series is very trust- 
worthy here, although carbolic solution has been employed ; the 
gaseous disinfectants, formaldehyde and sulphurous acid, are much more 
efficient. For the disinfection of the excrementa, crude carbolic acid 
and tar have been advocated. 

2. To Prevent the Infection of Wounds in surgery. This was first 
attained by Lister's carbolic acid dressing and operative procedure, 
but many other antiseptics have since been substituted for carbolic 
acid, and the use of antiseptics during operations on uninfected organs 
has given way to the aseptic method. For use during operations on 
infected wounds, the disinfectant must be soluble or miscible in water, 
and ought to produce as little irritation as possible, but there is less 
likelihood of serious poisoning or irritation from the use of antiseptics 
here than from their subsequent application to the wounded surface as 
dressings. The importance of avoiding the use of irritant antiseptics 
in operations on delicate structures, such as the peritoneum, has only 
been fully recognized of late years. Where a dressing has to be applied 
for some time, and especially when the wounded surface is large, as in 
the case of burns or large abscesses, the danger of absorption has to be 
taken into consideration, and antiseptics ought therefore to be chosen 
which are either absorbed slowly or are not very poisonous to man. 
The frequent occurrence of more or less severe carbolic intoxication 
has led to its employment being much more restricted than formerly, 
while the less soluble or less poisonous antiseptics have taken its place. 

3. In the Treatment of Skin Diseases the danger of absorption is even 
greater than in the dressing of wounds, as the absorbing surface is often 
very much more extensive, and in addition the more irritant antiseptics 
are obviously not admissible here. In many cases of successful treat- 
ment with bodies of the aromatic series, the remedy seems to act not only 
as an antiseptic but also as a mild irritant and astringent. Pyrogallol 
is believed by some dermatologists to be of value only from its reduc- 
ing action depriving the superficial tissues of their oxygen. 

4. The antiseptics have been frequently employed for their Disin- 
fectant Action on the Bowel, and as far as the putrefaction of the in- 
testinal contents is concerned, with success. The disintegration of the 
food by microbes in the bowel may be estimated by the amount of 
double sulphates appearing in the urine, and in several series of exper- 
iments these have been found to be notably diminished by bodies of 
the aromatic series. Fewer microbes have been found in the faeces 



ANTISEPTICS OF THE AROMATIC SERIES. 395 

also after these antiseptics have been administered. When, however, 
bacterial infection of the wall of the bowel is treated with these anti- 
septics, the results are less favorable. In typhoid fever, in which the 
subject has been most frequently examined, the number of the typhoid 
bacilli in the stools has not been lessened to any noticeable extent, and 
the majority of clinical observers seem to be very sceptical as to any 
relief of the symptoms being attained or of the duration of the dis- 
ease being shortened by their use. 

Any drug used for the disinfection of the intestine must not be irri- 
tant, nor very poisonous. It must not be too soluble, since otherwise 
it may be absorbed from the stomach and fail to reach the bowel, and 
on the other hand it must be soluble to some extent, or it cannot mix 
very intimately with the contents of the intestine. Carbolic acid is 
scarcely fitted for this purpose, for it irritates the stomach and is also 
rapidly absorbed. Some of the cresols have been recommended of late 
years, and the naphtalin preparations have also enjoyed some repu- 
tation. Salol and its congeners have the advantages of being almost 
completely insoluble and harmless in the stomach and of being dis- 
solved and rendered active by the intestinal juices, and have been 
found of value in excessive putrefaction of the contents of the bowel. 
It has to be added that putrefaction in the bowel is best treated by its 
evacuation by a purgative, such as one of the mercurial preparations, 
which also have a high antiseptic value. 

5. The antiseptics of the benzol series are excreted in great part by 
the kidneys, and the urine is thus rendered weakly antiseptic and 
irritant. This fact has been taken advantage of in the treatment of 
Septic Diseases of the Bladder and Urethra ; the drugs used for this pur- 
pose must not be too irritant to the gastric mucous membranes, and 
must be easily absorbed, and not dangerously poisouous. Here, again, 
salol has been found of value as well as salicylic acid. The forms in 
which the benzol derivatives are excreted by the kidney are generally 
much less irritant and antiseptic than that in which they are adminis- 
tered. In estimating the value of each as a urinary disinfectant, it 
must also be remembered that many of them are liable to undergo 
oxidation in the urine itself. 

6. Small quantities of some of the more volatile members of this series, 
especially of the hydrocarbons, escape by the lungs, and this has led 
to their use in Pulmonary Disease, especially in phthisis. It may be 
stated at once that careful observers are almost all united in the belief 
that the internal administration of these remedies has practically no 
antiseptic effect on the microbes in the lungs. Some relief is often ob- 
tained, but, it is believed, only through their disinfectant action in the 
stomach and bowel. Antiseptic remedies have also been inhaled in 
vapor or spray and have been injected into the trachea and even into 
the lung directly, but as far as the tubercle bacillus is concerned, they 
have had no result in the hands of the vast majority of physicians. In 
cases of gangrene of the lung, foetid bronchitis, etc., the inhalations re- 
lieve the patient to some extent, and certainly lessen the offensive odor. 



396 ORGANIC DRUGS ACTING AFTER ABSORPTION 

7. The use of antiseptics to Destroy Pathogenic Germs in the Tissues 
after Absorption is very limited. It is now recognized to be hopeless to 
attempt to find a single body which will destroy all forms of bacteria in 
the tissues, while leaving the host uninjured, but there is still reason 
to believe that in the future specific antiseptics may be found for at 
least some of the constitutional diseases. Such a specific action is 
seen in the effects of quinine on the organism of malaria, of salicylic 
acid in rheumatic fever, and of mercury in syphilis, all of these ap- 
parently acting more strongly on the cause of the disease than on the 
tissues of the patient. While it may be hoped that the antiseptic 
treatment of internal maladies has not reached its final limit, the only 
constitutional disease in which the aromatic series has been shown to 
be of incontestable value is acute rheumatism, and in many other 
conditions which were formerly treated with benzol antiseptics, they 
have proved rather injurious than otherwise. Even the least danger- 
ous cause symptoms of poisoning in much smaller quantities than 
would be necessary to render the blood an antiseptic solution. 

There is reason to believe that solutions containing several of the 
benzol series are more strongly antiseptic than those containing an 
equal percentage of the individual pure bodies, and that the mixture 
of such a body as carbolic acid with an antiseptic of another kind, 
e. g., mercuric perchloride, is still more efficient than the correspond- 
ing proportion of either alone. This appears to be due to a change in 
the solubility of the disinfectant, at any rate in some cases. If a 
poison is to penetrate into the interior of an organism in quantity it 
must be as soluble in the protoplasm as in the fluid in which it is ap- 
plied, for it is obvious that it will not leave a medium in w T hich it is 
readily soluble for one in which it is dissolved with difficulty. Ac- 
cordingly it is found that fats and oils in which the members of the 
aromatic series are very soluble are not suitable as media for their ap- 
plication, for the poisons remain in the oily menstruum and fail to 
penetrate the microbes in which they are less soluble. On the other 
hand, the addition of inorganic salts to an aqueous solution of carbolic 
acid often increases its antiseptic power, because the poison becomes 
less soluble in the water and shows a greater tendency to escape from 
it into the interior of the microbes. 

Fate in the Tissues. — The fate of the members of the aromatic series 
in the body is very uniform in one respect — the benzol ring is rup- 
tured only with great difficulty. In the great majority of cases the 
changes which these substances undergo in the tissues affect only the 
hydrogen or the side chains attached to the carbon atoms, and leave 
the form in which these last are attached to each other unchanged. 
The chief exceptions to this rule are pyrogallol and gallic acid, which 
seem to undergo more or less complete oxidation to carbonic acid and 
water. Some oxidation takes place in the aromatic series, however, 
the simpler forms, such as benzol and aniline, tending to form hydroxyl 
compounds, while those with a side chain formed of methane deriva- 
tives tend to oxidize it to carboxyl. The oxidation of the benzol com- 



ANTISEPTICS OF THE AROMATIC SERIES. 397 

pounds, in the tissues therefore results in the formation of oxybenzols 
and aromatic acids, and this oxidation is probably not limited to any 
one particular tissue or organ. These bodies are not, however, ex- 
creted in this form in ordinary cases, but enter into secondary combi- 
nations in which they appear in the urine. The hydroxyl bodies 
unite with sulphuric and glycuronic acids to form double sulphates 
(ether-sulphuric acid salts) and glycuronates, while the aromatic acids 
are excreted in combinations with glycocoll, which are known as hip- 
puric, salicyluric, etc., acids. The last synthesis probably occurs 
chiefly in the kidney, while the double sulphates are said to be formed 
in the liver. 

A few examples of the changes undergone in the tissues may elu- 
cidate the above statement. Benzol (C 6 H 6 ) is oxidized to phenol 

(C 6 H 5 OH), and to dioxybenzols (C 6 H 4 < OH I , which combine in the 

kidney with sulphuric and glycuronic acids to form phenol-sulphuric 
(C 6 H s O — S0 3 H) and phenol-glycuronic acids, and the correspond- 
ing dioxybenzol compounds. Toluol (C 6 H 5 — CH 3 ) is oxidized to 
benzoic acid (C 6 H 5 — COOH), which combines with the glycocoll of 
the body to form hippuric acid (C 6 H 5 CO— NHCH 2 COOH). Xylol 

(pTT v 
C 6 H 4 <p TT 3 J is oxidized only in one side chain and forms toluic acid 

(PTT \ 
C 6 H 4 <p ^- H - 1 , which is excreted in combination with glycocoll as 

toluic acid. 

Although a general resemblance exists in the oxidation products of 
these bodies in the tissues and in the forms in which they are excreted, 
considerable differences are noted in the details. Thus, naphtalin 
undergoes the same oxidation as benzol, forming naphtol in place of 
phenol, but while the phenol appears in the urine in combination with 
sulphuric acid almost entirely, the naphtol combines with glycuronic 
acid for the most part. 

Bibliography. 

Consult that given under the individual members — Carbolic Acid, Salicyclic 
Acid, etc. 

Antiseptic Action. 
DougaU. Med. Times and Gazette, 1872, i., p. 495. 
Grace Calvert. Ibid., p. 176. 

Bucholtz. Arch. f. exp. Path. u. Pharm., iv., p. 1. 
Haberkorn. Inaug. Diss., Dorpat, 1879. 
Krajewski. Arch. f. exp. Path. u. Pharm., xiv., p. 139. 
Koch. Mittheilung aus dem Kaiserlich. Gesundheitsamt., i., p. 234. 
Jalan de la Croix. Arch. f. exp. Path. u. Pharm., xiii., p. 175. 
Cash. Reports of British Local Government Board, 1886. 
Sternberg. Bull, of National Board of Health, 1881. 
Schulz. Pfliiger's Arch., xlii., p. 517. 
Biernacki. Ibid., xlix., p. 112. 
Kronig u. Paul. Ztschr. f. Hygiene, xxv., p. 1. 
Spiro u. Bi-uns. Arch. f. exp. Path. u. Pharm., xli., p. 353. 



398 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

General Action. 

Brunton and Cash. Proc. Roy. Soc, xlii., p. 240. 

Schultzen u. Graebe. Arch. f. Anat. u. Phys., 1867, p. 166. 

Schultzen u. Naunyn. Ibid. , p. 349. 

Nencki. Ibid., p. 399, 1870. 

Baumann. Pfliiger's Arch., xiii., p. 285. 

Baumann u. Preusse. Arch. f. Anat. u. Phys., 1879, p. 245. 

Baumann and pupils. Zts. f. phys. Chem., i.-vii. 

Bokorny. Pfliiger's Arch., lxiv., p. 306. 

Nencki u. Giacosa. Zts. f. physiol. Chem., iv., p. 325. 

Nencki. Arch. f. exp. Path. u. Pharm., i., p. 420 ; xxx., p. 300. 

Karpow. Arch, des Sciences Biolog. , ii., p. 305. 

Ziegler. Arch. f. exp. Path., i., p. 65. 

Steiff. Zts. f. klin. Med., xvi., p. 311. 

Binet. Trav. de Labor, de Therap. exp. de Geneve, ii., p. 143. 

Schmiedeberg. Arch. f. exp. Path. u. Pharm., xiv., p. 379. 

1. Carbolic Acid. 

Carbolic acid or phenol, the first of the modern antiseptics to be in- 
troduced, acts like the rest of the simpler benzol compounds as a 
General Protoplasm Poison, although in the vertebrates it acts more 
powerfully on the central nervous system than on the other tissues. 

Its poisonous effects are well seen when it is applied to unicel- 
lular organisms such as the protozoa. Even dilute solutions cause 
immediate arrest of all movements ; the organism assumes a spherical 
shape and loses its transparency, and, unless the solution be very 
attenuated, dies in the course of a few minutes. Plant cells are acted 
on in the same way, and the individual cells of more highly organized 
animals, such as the ciliated epithelium of the air passages and the 
spermatozoa, are killed at once when brought in contact with carbolic 
acid. There is some evidence, however, that very dilute solutions of 
carbolic acid, as of other antiseptics, tend to increase the activity of 
protoplasm. Thus Biernacki and Schulz have found that while solu- 
tions of phenol, such as are used as surgical antiseptics, are immediately 
fatal to the yeast plant, very dilute solutions increase its activity. The 
effect of carbolic acid on protoplasm has, however, been studied chiefly 
in the bacteria. Its antiseptic power, while always considerable, is 
found to vary greatly with the species of microbe. Thus, while it is 
fairly poisonous to the ordinary pyogenic organisms, it has to be present 
in very concentrated form to destroy the more resistant spores of an- 
thrax, and like other antiseptics, is much less poisonous to the 
microbes than to the protozoa and other simple forms of life. The 
development and reproduction of many microorganisms has been found 
to be much delayed, or altogether prevented, as long as they remained 
in a solution of one part of carbolic acid in 400-600 parts water, but 
in order to kill the spores very much more concentrated solutions (5 
per cent.) were required, and Koch found that the spores of the 
anthrax bacilli were destroyed by 5 per cent, carbolic solution only 
after they had remained in it for two days. 

It seems to vary considerably in its action on the unorganized fer- 
ments ; thus it is said not to retard appreciably the fermentations 



ANTISEPTICS OF THE AROMATIC SERIES. 399 

produced by emulsin, diastase and myrosin, even when present in the 
solution up to 5 per cent., while pepsin, ptyalin and the rennet fer- 
ment are weakened by somewhat smaller quantities. 

Carbolic acid precipitates Proteids in solution and also in the cells. 
It does not seem to enter into any such firm combination with them as 
is formed when tannic acid or a salt of one of the heavy metals is added 
to a solution of proteid, for it can be washed out of the precipitate 
with comparative ease. Its action in precipitating albumins may 
rather be compared to that of alcohol, in which the proteid is precipi- 
tated, not because an insoluble compound is formed, but because of a 
change in the nature of the solvent. It results from this that carbolic 
acid penetrates more thoroughly than the metallic antiseptics, which 
are rendered insoluble by the albumin they meet, and whose action 
therefore tends to remain confined to the surface. 

This coagulation of the proteids occurs whenever carbolic acid is 
brought in contact with the tissues. On the Skin a white, opaque scar 
is formed by concentrated phenol, which becomes red and shining af- 
terwards and then falls off in a few days, leaving a light brown stain 
which may remain for several weeks. Even a five per cent, solution 
applied to the fingers produces tingling and warmth, which is often fol- 
lowed by opacity and shrinking of the epidermis and a sense of numb- 
ness. This numbness may amount to almost complete anaesthesia if 
more concentrated solutions are applied, no pain being felt even when 
the skin is cut through. When applied for some time and prevented 
from evaporating, carbolic acid may cause extensive dry gangrene of 
the part from its penetrating through the surface layer and reaching the 
deeper tissues. Applied to a Wound in five per cent, solution, phenol 
induces pain and irritation and the formation of a white pellicle of 
coagulated proteids. It causes irritation and necrosis of the Mucous 
Membranes, and if applied in sufficient quantity may be followed by 
sloughing and acute inflammation. This local effect may prove fatal 
from shock and collapse when large quantities of the undiluted acid 
are swallowed, the effect resembling exactly that produced by other 
corrosive substances. 

Apart from its local action, carbolic acid has important effects after 
its absorption into the blood. The most marked of these are the 
changes in the Central Nervous System. When a small quantity of 
carbolic acid is injected into the frog, the first symptoms, apart from 
those produced by the pain of the injection, consist in an unusual quiet 
and in the absence of the spontaneous movements. Later, quivering 
of individual muscles, and apparently of the individual bundles of 
muscle fibres, sets in, and this is soon accompanied by an increase in the 
reflex irritability and eventually by convulsions similar to those seen 
after strychnine. These movements gradually become weaker, and 
eventually complete paralysis is induced, while the heart continues to 
beat and the muscles and nerves react to the electric shock. A dilute 
solution of carbolic acid applied directly to the exposed spinal 
cord paralyzes the sensory elements immediately, while leaving 



400 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

unaffected the motor fibres and the cells of the anterior horn (Bag- 
lioni). 

In mammals, a very similar set of symptoms are produced, save that 
there is often no noticeable preliminary stage of depression. Some 
weakness and lethargy may be present, however, and are followed by 
marked muscular tremor, which resembles the shivering produced by 
cold. At intervals this is interrupted by sudden twitches in different 
muscles, and later by clonic convulsions. The respiration and the 
pulse are at first accelerated, but afterwards are slow, irregular, and 
weak. The movements become feeble and appear at longer intervals, 
the respiration is shallow and irregular, and the animal passes into a 
condition of collapse, in which, however, the sensibility to pain is often 
preserved. Eventually death occurs from asphyxia. After very large 
doses the collapse may be immediate, no convulsions being observed, 
the heart and respiration often ceasing simultaneously. In most cases 
salivation is a marked symptom, and the temperature often falls far 
below the normal. 

In man, convulsions are comparatively rarely seen. When large 
quantities are taken, immediate unconsciousness may result and death 
follow within a few minutes. How far this is due to the local cor- 
rosion, and how far the direct action on the central nervous system is 
involved, cannot be determined. In more gradual poisoning, de- 
pression and weakness, headache, nausea and vomiting are followed by 
giddiness, noises in the ears, pallor and collapse, with irregular pulse 
and respiration, and cold perspiration ; fainting and unconsciousness 
then lead to failure of the breathing, and death. Delirium and excite- 
ment have been observed in some cases. Fatal poisoning may arise 
from swallowing the concentrated or dilute solution, or from absorption 
from wounds and abscesses. It has also occurred in man from absorp- 
tion through the unbroken skin. 

The autopsy sometimes gives no special indications of the cause of 
death, save the local corrosion of the alimentary canal. Inflammation 
and necrosis of the intestine is said to have been observed in some 
cases in which the poison was absorbed from skin wounds, and fatty 
degeneration is sometimes induced in the liver and the renal epithelium, 
but is not constant. 

The cause of the convulsions in the frog seems to be an increase in 
the irritability of the spinal cord similar to that seen in strychnine, 
for they are not removed by section of the medulla oblongata. In 
mammals the sudden contractions of isolated muscles appear due to a 
similar action on the spinal cord, but the clonic convulsions and the 
persistent tremors are probably of cerebral origin, and Berkholz found 
the cerebral cortex abnormally irritable after carbolic acid. The rarity 
of convulsions in man has not been satisfactorily explained. In some 
cases the course of the intoxication is too short, the large amount of 
poison swallowed inducing immediate collapse, while in others their 
absence may be due to the debility of the patient from disease ; but 
in a considerable number of cases of poisoning in which neither of 



ANTISEPTICS OF THE AROMATIC SERIES. 401 

these conditions was present, no convulsions were observed. A sim- 
ilar contrast between the effects of a poison on the lower animals and 
on man has been mentioned already under morphine. In all cases, 
the primary stimulation of the central nervous system is followed by 
depression and paralysis if large doses are administered. 

The acceleration of the Respiration and of the Heart seen in mam- 
mals has been supposed to be an indirect result of the increased mus- 
cular movement and convulsions, but this seems to be incorrect, for 
the heart is found to be accelerated before the convulsive movements 
and tremor appear, and the frog's heart is accelerated in cases where 
no movements occur whatever. It would seem probable that the 
acceleration of the heart is due to direct action on the muscle or on 
the regulating nerves. The subsequent slowing is undoubtedly due to 
muscular action. 

The acceleration of the respiration precedes the increased move- 
ment also, and would therefore seem to be due to action on the med- 
ullary centre, which is first stimulated and later paralyzed. The 
vaso-motor centre is said by Gies to be depressed at once by the injec- 
tion of carbolic acid into the blood, but it may be questioned whether 
it too is not first excited when the poison is absorbed more slowly. 
It is undoubtedly depressed in the later stages of poisoning, and this, 
together with the weakness and slowness of the heart, causes a fall in 
the blood-pressure. 

The peripheral Nerves and Muscles do not seem to be affected in 
general poisoning in mammals, although in the frog their irritability 
and the capacity for work of the muscle may be somewhat reduced. 

On the direct application of solutions of carbolic acid to the nerves 
or muscles, these are at once killed, like other forms of living matter. 

The increased Secretion of saliva, perspiration and tears which is 
seen in poisoning in mammals is probably of central origin, and may 
possibly be associated with the nausea and vomiting. 

The fall in Temperature in carbolic acid poisoning seems, for the 
main part, to be due to the collapse, although it is impossible to state 
how far this may be aided by some alteration of the regulating func- 
tion, such as is seen in the closely related group of the antipyretics. 

Carbolic acid added to the defibrinated Blood leads to the slow forma- 
tion of inet haemoglobin, but this does not occur in the living animal. 
Occasionally some destruction of the red blood cells is caused in 
animals through the injection of carbolic acid directly into the blood 
vessels, and in one case of poisoning in man haemoglobin was detected 
in the urine, indicating that some of the red cells of the blood had 
been destroyed. 

Excretion. — Ca bolic acid passes through the tissues unoxidized for 
the most part, but a certain proportion of it undergoes a partial oxida- 
tion to hydroquinone and pyrocatechin. These combine in the body 
with sulphuric and glycuronic acids, and are excreted in the urine as 
double sulphates (ether sulphates) and glycuronates of phenol, hydro- 
quinone and pyrocatechin. The two last-named bodies are somewhat 
26 



402 ORGANIC DRUGS ACTING AFTER ABSORPTION 

unstable, and tend to undergo further oxidation, through which colored 
substances are formed. When carbolic acid has been absorbed, there- 
fore, the urine tends to assume a dark, dusky-green color which may 
change to brown or even black. This change may occur in the body, 
and the urine is very often passed of a greenish-brown color, but further 
oxidation takes place on exposure to the air, resulting in deeper colora- 
tion which commences at the surface of the fluid and gradually extends 
downwards. The depth of the shade depends not on the amount of 
phenol sulphate in the urine, but on that of the dioxybenzols, and a 
darker urine is often observed, therefore, when the absorption has oc- 
curred from an open wound (in which the conditions are especially 
favorable to oxidation) than from much larger quantities absorbed 
from the alimentary canal. 

The presence of glycuronates in the urine may lead to its reducing 
Fehling's solution, and thus give rise to the suspicion of glycosuria. 
On the other hand, the passage of these bodies through the kidney 
often causes some irritation and albuminuria. The double sulphates 
of the urine are, of course, much increased, and in the dog the whole 
of the ordinary inorganic sulphates may disappear, the urine contain- 
ing only double sulphates. 

The Chlorphenols, in which chlorine is substituted for one or more of the 
hydrogen atoms of carbolic acid, are much more poisonous to microorgan- 
isms than the original substance, but are also somewhat more poisonous to 
mammals, so that they have not been much used. A similar intensifying 
effect is seen in the chlorine substitution products of the narcotic series, e. g., 
chloroform. The most poisonous of the monochlor-phenols is parachlorphenol. 
Bromol or tribromphenol has been used to a limited extent in therapeutics 
as a disinfectant and caustic. 

Preparations. 

Acidum Carbolicum Crudum (U. S. P.) contains other phenols and cresols, 
as well as carbolic acid. 

Acidum Carbolicum (U. S. P., B. P.), carbolic acid or phenol (C 6 H.OH) 
forms colorless, deliquescent crystals when recently prepared, but often 
assumes a reddish tinge from oxidation. It has a characteristic odor and is 
intensely corrosive. It is soluble in about 15 parts of water, but becomes 
liquid when 10 parts of water are added to 90 of the crystals, forming the 
Acidum Carbolicum Liquefactum of the B. P. This must be carefully distin- 
guished from the ordinary solution of carbolic acid, which contains only 
about 5 per cent, of phenol, while the liquefied carbolic acid contains 90 per 
cent. 

Carbolic acid, 0.03-0.2 G. (J-3 grs.). 

Liquefied carbolic acid, 1-3 rains. 

Glyceritum Acidi Carbolici (U. S. P.), Glycerinum Acidi Carbolici (B. P.), 
20 per cent, of carbolic acid in glycerin. 

Unguentum Acidi Carbolici, TJ. S. P., 5 per cent.; B. P., 4 per cent. 

Trochiscus Acidi Carbolici (B. P.), each containing 1 gr. 

Suppositoria Acidi Carbolici (B. P.), each containing 1 gr. 

Therapeutic Uses. — Carbolic acid is used as an antiseptic in surgical 
operations in 2-5 per cent, solution in water. It now plays a much 
less important role in surgery than it did in the first days of and- 



ANTISEPTICS OF THE AROMATIC SERIES. 403 

sepsis ; in fact, in many clinics in which it was once the only anti- 
septic used, and in which it was applied in all the manifold prepara- 
tions then known, carbolic acid is now employed only to preserve the 
instruments from infection. This change is no doubt partially due to 
apprehension of its irritant action, and to the occasional cases of pois- 
oning which occurred from its use, but chiefly to the alterations in 
surgical technique which have been introduced since the antiseptic 
method was first invented. The tendency now is to reduce the use of 
antiseptics to a minimum and to trust instead to stricter cleanliness 
and asepsis. Its irritant action and the danger of absorption have 
also rendered it unpopular as a dressing or lotion after operations or 
injuries, where there is any large absorbent surface, or where irritation 
is liable to be injurious, as in most forms of skin disease. 

It is still used as a disinfectant in septic wounds, though greater 
reliance is now placed on corrosive sublimate and the oxidizing anti- 
septics such as hydrogen peroxide. Strong carbolic acid has been 
applied to disinfect wounds, its poisonous effects being avoided by im- 
mediately washing it off with alcohol. 

Harrington has recently drawn attention to the danger of applying 
dilute solutions in bandages to injured fingers and hands ; he found 
records of over a hundred cases in which this had led to gangrene 
necessitating amputation. 

Carbolic acid has also been employed as a caustic, the liquefied 
preparation being preferred for this purpose. It is less painful than 
other caustics owing to its anaesthetizing action, but it is also less 
efficient. 

Its local action on the sensory nerve terminations has been utilized 
in itching skin diseases and it may be noted that some recent local 
anaesthetics are benzol derivatives (see page 314). The treatment 
of deep-seated abscesses and inflammation by the local injection of 
carbolic acid solutions has passed into desuetude, and a similar fate 
has befallen its use to limit the extension of erysipelas. The spray of 
carbolic acid has been advised in laryngeal and pulmonary disease, but 
is scarcely met with in recent years. A solution of carbolic acid has 
been employed as an irritant to cause inflammatory reaction, cicatricial 
adhesion and consequent obliteration of small cysts, such as hydrocele, 
and in naevus. 

Internally carbolic acid was tried as an intestinal disinfectant, and 
in many infectious fevers. It causes marked irritation of the stomach, 
however, and probably little of it reaches the bowel, as it is rapidly 
absorbed, and other less irritant and less soluble bodies have therefore 
been substituted for it. Its use as a remedy in constitutional diseases 
is entirely obsolete. 

It may be prescribed as a pill or in capsules for internal use, as the 
solutions are more liable to cause irritation ; only the pure acid is 
prescribed either for internal or external application. Crude carbolic 
acid may be employed to disinfect stools, latrines, etc., and is quite 
unsuited for therapeutic use. The ointment is comparatively seldom 



404 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

prescribed, as it is found more irritant than many other equally power- 
ful antiseptics. The glycerite may be used as a very weak caustic. 
Solutions of carbolic acid in oil have little or no antiseptic action, 
because they fail to penetrate into the microbes. 

Poisoning. — In carbolic acid poisoning, when it has been taken by 
the mouth, the first treatment is the removal of the poison by the 
stomach tube, and the administration of demulcents such as white of 
egg ; when absorption has occurred from the skin or from a wound, 
the dressing should be removed at once. Lime suspended in syrup 
has been recommended in cases in which the acid has been swallowed, 
in the hope that an insoluble combination may be formed in the stom- 
ach. The combination of phenol with sulphuric acid in the tissues 
forms a comparatively harmless body, and Baumann and Preusse there- 
fore suggested the administration of sodium sulphate in large quanti- 
ties. It is found, however, that this is of little or no use, either because 
the tissues in which the synthesis occurs are entirely paralyzed by the 
excess of phenol, or more probably because the phenol does not combine 
with sulphates as such in the body, but with organic sulphur com- 
pounds which are only in process of being oxidized to sulphuric acid. 
When coma and collapse set in, the patient is to be sustained by the 
application of warmth externally, and by the administration of such 
central nervous stimulants as caffeine, atropine, or camphor ; artificial 
respiration may eventually be used, although there is little prospect 
of resuscitation if the intoxication has advanced so far. The corrosion 
induced by carbolic acid locally may be treated by washing the part 
with alcohol which dissolves the acid readily. This treatment has 
been suggested for cases in which the poison has been swallowed, but 
it does not seem to prevent poisoning in animals. 

Bibliography. 

Lemaire. L'acide phenique, de son action sur les vegetaux, etc. Paris, 1865. 
Neumann. Arch. f. Dermat. u. Syphilol., i., p. 425. 

Husemann. Deutsche Klinik, 1870, 1871. Arch. f. exp. Path. u. Pharm., iv., p. 280. 
Gies. Ibid., xii, p. 401. 

Baumann and his pupils. Pfliiger's Arch. , xiii., p. 285. Zts. f. phys. Chem., i., 
p. 244 ; ii., pp. 273, 350 ; iii., pp. 156, 177. Arch. f. Anat. u. Phys., 1879, p. 245. 
Bill. Amer. Jour, of Med. Sci., lxiv., p. 17. 
Salkowsky. Pfliiger's Arch., v., p. 335. 
Hoppe-Seylor. Ibid., v., p. 470. 
Plugge. Ibid., v., p. 538. 

Prudden. Am. Jour, of Med. Sci., lxxxi., p. 82. 
Tauber. Arch. f. exp. Path. u. Pharm., xxxvi., p. 197. 
Schmiedeberg. Ibid., xiv., p. 288. 
Turtschaninow. Ibid., xxxiv., p. 208. 

Berkhoh. See Unverricht, Centralb. f. inn. Med., 1895, p. 4. 
Baglioni. Arch. f. [Anat. u.] Phys., 1900, Supplem., p. 193. 
Minervini, Arch. f. klin. Chirurg., lx., p. 687. 
Harrington. Am. Jour, of Med. Sci., cxx., p. 1. 

Cresol. 

The three cresols are nearly related to carbolic acid chemically, and re- 
semble it very closely in their effects . Metacresol is less poisonous to mam- 



ANTISEPTICS OF THE AROMATIC SERIES. 405 

mals and less irritant, and at the same time seems to be more destructive to 
microbes than carbolic acid. Orthocresol is more dangerous than carbolic 
acid, and paracresol is the most powerful poison of all. The symptoms 
produced by these bodies are identical with those of phenol. They are ex- 
creted as cresol double sulphates mainly, but some appears in the urine as 
the sulphate of a more highly oxidized form, dioxytoluol. The cresols are 
constituents of the tars and other crude antiseptic substances. They are 
only slightly soluble in water, and there has been some difficulty in render- 
ing them available for surgical use, but this has been overcome by forming 
emulsions {creolin), or by dissolving them with the aid of salts (solveol, sol- 
utol) or suspending them by means of soap (lysol). These are not claimed 
to be pure preparations of cresol, but the three isomeric cresols have recently 
been introduced as tricresol, which dissolves in water to the extent of 2£ per 
cent. These preparations are not devoid of poisonous properties, as is often 
stated by interested individuals, but they are not so dangerous as carbolic 
acid. They are used chiefly as surgical antiseptics, but creolin has also been 
given as an intestinal disinfectant, although with indifferent results. Their 
value as surgical antiseptics has been denied by some writers and there is no 
question that it has been much overrated by others. Kresamine (ethylendi- 
amine and tricresol) is said to be more strongly antiseptic than tricresol, and 
has been recommended in diseases of the skin as an ointment or solution. 

Anisol and Phenetol, the ethers of carbolic acid, resemble it in their effects 
and have no practical or theoretical interest. 

Bibliography. 

Seybold. Ztschr. f. Hygiene, xxix., p. 377. 

Thymol. 

Another phenol homologue is thymol, which resembles carbolic acid 
closely in its action, though it causes less central nervous stimulation. Con- 
vulsions aud tremors are rarely induced in either frogs or mammals, and 
when present, are very much less intense than those following carbolic acid. 
The animal generally sinks into a condition of apathy and weakness, which 
gradually passes into collapse and death. Thymol is less soluble in the 
fluids of the body, and is therefore absorbed more slowly than carbolic acid. 
It is also less irritant to wounded surfaces and is, according to most observ- 
ers, considerably more poisonous to putrefactive organisms, while less pois- 
onous to the higher animals. In poisoning from its use, fatty degeneration 
of the liver, marked congestion and even consolidation of the lungs, and ir- 
ritation of the intestines have been observed. It is excreted in the urine in 
combination with sulphuric and glycuronic acids, partly unchanged, partly 
oxidized to thymolhydroquinone. There is also found in the urine a green 
coloring substance, which becomes blue on the addition of acid, and which 
seems nearly related to, but not identical with indigo. Thymol is said to 
be more liable to cause renal irritation than carbolic acid and albumin and 
even blood have been repeatedly observed in the urine after its absorption. 

Thymol (U. S. P., B. P.) (C 6 H 3 C 3 H 7 CH 3 OH) occurs in common thyme 
and several other plants, and forms large, colorless crystals, which have the 
odor of thyme and are very insoluble in water. 0.03-0.2 G. Q-3 grs.) in 
pills or in solution in dilute alcohol. 

Thymol seems to have some advantages over phenol as a surgical disin- 
fectant, but has never attracted much attention, though it has been used oc- 
casionally as an antiseptic lotion in T \$- per cent, solution. As an internal 
remedy it has proved a failure in the treatment of various constitutional dis- 
eases, such as acute rheumatism, phthisis and typhoid fever. It is said to 
have some value as an intestinal disinfectant and anthelmintic, and lias 
been used as an antiseptic mouth-wash and gargle, for which carbolic acid 
is rendered unsuitable by its unpleasant odor and its corrosive action. 



406 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

Bibliography. 

Husemann. Arch. f. exp. Path. u. Pharm., iv., p. 280. 

Blum. Zts. f. physiol. Chem., xvi., p. 514. Deutsche med. Woch., 1891, p. 186. 

Lewin. Virchow's Arch., lxv., p. 164. 

Baelz. Arch, der Heilkunde, xviii., p. 60. 

Kuessner. Habilitationschr., Halle, 1878. 

Eucalyptol. 

Eucalyptol (C 10 H 18 O) is the chief constituent of oil of eucalyptus, which 
is obtained from Eucalyptus globulus and some other species. It is also 
contained in the oil of cajuput and in other volatile oils. It has been re- 
commended as a surgical antiseptic and in the same class of internal diseases 
as thymol, but does not seem to have any special virtues distinguishing it 
from the general class of volatile oils. 

Eucalyptol (IT. S. P.), a colorless fluid, having a characteristic, camphor- 
aceous odor and a pungent, spicy, cooling taste. It is almost insoluble in 
water, but is miscible with alcohol in all proportions. 

Resorcin. 

The three dioxybenzols — resorcin, pyrocatechin and hydroquinone — re- 
semble carbolic acid in their effects, but produce a more intense stimu- 
lation of the central nervous system, for convulsions have been observed in 
man after their use. This is especially true for the two last, resorcin being 
much less toxic than these. Kesorcin seems to be equally or more strongly 
antiseptic than phenol, and is somewhat less poisonous, while the others are 
more dangerous ; it is less irritant and caustic than carbolic acid. All three 
dioxybenzols are excreted in the urine in combination with sulphuric and 
glycuronic acids. They are in part subjected to further oxidation, leading to 
coloration of the urine similar to that seen in carbolic acid poisoning. Pyro- 
catechin and hydroquinone when added to blood form methsemoglobin much 
more readily than phenol, and also tend to form it in the body when the 
intoxication does not progress too rapidly to allow of this alteration in the 
living animal. They cause a much greater destruction of the red blood cells 
than phenol. 

Resorcinum (TJ. S. P.), resorcin, metadioxybenzol (C 6 H 4 (OH) 2 ), colorless, 
very soluble crystals, with a faint aromatic odor. 0.3-0.6 G. (5-10 grs.) ; 3 
G. (45 grs.) in 24 hours. 

Eesorcin is a remedy which has fallen into almost complete disuse. At 
first introduced as an antiseptic, it was prescribed for a short time as an 
antipyretic, but has proved as unsuitable for this purpose as carbolic acid or 
aniline, which reduce fever temperature, but cause symptoms of collapse very 
readily. It has been used as an intestinal antiseptic and in rheumatic fever, 
but has here again been supplanted by less dangerous remedies. As an ex- 
ternal application, it has been applied in ointment (5-10 per cent.) in skin 
diseases, and has been injected in cystitis and gonorrhoea in solution (1-3 
per cent.) but in both cases is liable to produce irritation and pain. As an 
internal remedy it should be prescribed in dilute solution (1-2 per cent.). 

Bibliography. 

Andeer. Centralbl. f. d. med. Wis., 1881-1889. 
Baumann. Zts. f. phys. Chem., i., p. 244. (See Carbolic Acid. ) 
Brieger. Zts. f. klin. Med., iii., p. 25. Arch. f. Anat. u. Phys., 1879, Suppl., P> 
61. 

Martin. Therap. Gaz., 1887, p. 289. 

Surbeck. Deutsch. Arch. f. klin. Med., xxxii. , p. 515. 

TJanilewsky. Arch. f. exp. Path. u. Pharm., xxxv., p. 105. 



ANTISEPTICS OF THE AROMATIC SERIES. 407 

2. Pyrogallol. 

Pyrogallol, the only trioxy benzol that has been largely used, pro- 
duces nervous symptoms resembling those of carbolic acid, when given 
in very large doses to animals, In the cases of poisoning which 
have been observed in man, the symptoms of which closely resemble 
those caused by smaller quantities in animals, these nervous symptoms 
have been almost entirely absent, and the poison acted not so much 
directly on the central nervous system, as upon the blood corpus- 
cles. Many of the other members of this series cause some destruc- 
tion of the red cells, but none of them approach pyrogallol in the inten- 
sity of their effects. The red blood cells become shrunken and angular 
aud lose most of their haernoglobiu, which escapes into the plasma and 
is changed into methsemoglobin ; the blood therefore assumes a brown- 
ish-red color, which may be detected in the living animal by the dis- 
coloration of the skin and mucous membranes. If the intoxication is 
not too acute, icterus follows, and haemoglobin and methaemoglobin are 
excreted in the urine. In the blood, fragments of red cells and 
" shadows/' or red cells deprived of their coloring matter, are seen in 
large numbers, and the spectrum of methaemoglobin can be obtained 
easily. The kidneys are also affected, and the resulting nephritis 
is indicated by the presence in the urine of albumin, epithelium, 
and casts, along with the products of the decomposition of the 
blood. The nephritis may lead to uraemic convulsions, which are 
Sometimes accompanied by the nervous tremors characteristic of this 
series, and also by dyspnoea and cyanosis from the lack of haemoglo- 
bin in the blood. The formation of methaemoglobin is generally be- 
lieved to be connected with the well-known reducing properties of py- 
rogallol, but whether the methsemoglobin is a direct result of the 
reduction caused in the haemoglobin, or whether a secondary oxidation 
accompanies this action, is unknown. Pyrogallol is excreted in part 
in combination with sulphuric acid in the urine, in part as unknown 
oxidized products, which give the urine a dark brown or black color, 
even when no blood pigments are contained in it. In fatal poisoning 
death seems to be due to the blood changes, and the consequent ne- 
phritis and jaundice, rather than to the direct effect of the drug on 
the central nervous system. It has been stated that the debris of the 
red blood cells fails to pass through the capillaries and thus leads to 
thrombosis, but this has been denied by later investigators. 

The skin is dyed brown when pyrogallol is applied to it, from the 
products of oxidation formed. 

Pyrogallol (U. S. P.), pyrogallic acid (CgH^OH),), light, colorless crystals 
or laminae when freshly prepared, which rapidly assume a darker color on 
exposure to light and air. It is very soluble in water and reduces the salts 
of the heavy metals even in the cold. It is used only externally. 

Pyrogallol is used in the treatment of several forms of skin disease, 
especially in psoriasis, in which it is applied in ointment (5-20 per 



408 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

cent.). It is dangerous to apply it to very large surfaces, however, 
and many authorities therefore advise the use of chrysarobin in its 
stead. Pyrogallol ought never to be used internally. Its curative 
action in skin diseases may be due to its slight irritant and antiseptic 
properties, but is referred by some to its reducing action. Gallaceto- 
phenone (CH 3 — CO — C 6 H 2 (OH) 3 ) has been recommended as a substi- 
tute for pyrogallol in skin affections. 

Bibliography. 

Wedl. Wiener Sitzungsber., lxiv., p. 405. 
Neisser. Zts. f. klin. Med., i., p. 88. 

Weyl u. Anrep. Arch. f. Anat. u. Phys., 1880, p. 234. 

Rekowski. Therap. Monatsch., 1891, p. 487. (Gallacetophenone. ) 

3. Naphtalin and Naphtol (Naphthol). 

Naphtalin and its compounds alpha- and beta-naphtol differ in some 
respects from the other members of the series. They are all insoluble 
in water, but the naphtols are dissolved in the alkalies. Some ques- 
tion has arisen as to whether Naphtalin is really an antiseptic in itself, 
or whether it owes its activity to the formation of the more 
soluble naphtols. Animals poisoned with it do not exhibit the ordi- 
nary symptoms of poisoning with an aromatic body, even when it is 
administered for several weeks, but suffer from diarrhoea and lose flesh 
rapidly, either from disturbance of the alimentary canal or from renal 
disorder. The urine soon contains albumin, casts and epithelium, and 
the kidney is found in a condition of parenchymatous nephritis. The 
changes in the eye caused by naphtalin and naphtol have excited some 
interest. The retina is seen with the ophthalmoscope to be dotted 
over with numerous bright points, or sometimes to contain large yellow 
plaques, and after large doses subretinal effusion has been observed. 
At the same time, atrophy of the optic nerve may occur, and bright 
points are seen in the vitreous humor similar to those in the retina. 
A slight cloudiness appears in the lens and increases rapidly until it 
becomes quite opaque and resembles an ordinary cataract in man. This 
does not seem to be secondary to the retinal changes, but is the result 
of an inflammatory infiltration beginning in the ciliary body and iris 
and extending into the lens and finally into the posterior surface of the 
cornea. These changes in the eye have generally been observed in 
animals treated with large doses of naphtajine or naphtol, and have not 
occurred in such intensity in man ; but v. d. Hoeve states that com- 
mencing retinal degeneration may be induced in man by the use of 
naphtol internally or externally and cautions against its prolonged ad- 
ministration. 

Large doses of the Naphtols induce symptoms similar to those of 
carbolic acid poisoning, except that in the dog no convulsions have 
been observed, and in the other mammals they seem less pronounced. 
They are irritating to the mucous membranes when they come in con- 
tact with them in solution or in vapor ; thus they cause sneezing and 



ANTISEPTICS OF THE AROMATIC SERIES. 409 

coughing when applied to the respiratory passages, and in the course 
of excretion induce pain in the bladder and urethra with strangury and 
swelling of the mucous membrane. Injected subcutaneously or ab- 
sorbed from the alimentary canal in animals, they induce acute nephritis 
with the appearance of albumin and haemoglobin in the urine, and 
some nephritis has been caused in man from their external application. 
They seem to have less effect on the circulation and respiration than 
the other aromatic antiseptics, but resemble them in tending to destroy 
the red cells of the blood. Alpha-naphtol has been found to be more 
strongly antiseptic than the beta compound, and may be more poison- 
ous, as is generally stated, but no satisfactory investigation has appeared 
regarding this point. Beta-naphtol is several times as strongly ger- 
micidal as carbolic acid, and is the form used in therapeutics. 

Naphtalin is partly oxidized in the tissues and appears in the urine 
as alpha- and beta-naphtol and naphtoquinone, all in combination with 
glycuronic and sulphuric acid. The naphtols are excreted in combi- 
nation with glycuronic acid mainly. These bodies and their oxidized 
products give the urine a reddish-brown tint, which may become 
deeper on exposure to the air, but in some cases it retains its ordinary 
color. 

Preparations. 

Napthalinum (TJ. S. P.), naphtalin or naphtalene (C 10 H 8 ), colorless, insolu- 
ble crystals with a coal-tar odor and a hot aromatic taste. 0.06-0.3 G. 
(1-5 grs.). 

Naphtol (U. S. P.), Naphthol (B. P.), Beta-naphtol (C 10 H 7 OH), white 
or yellowish-white, insoluble crystals or powder, with a faint phenol odor 
and a hot taste. 0.2-0.6 G. (3-10 grs.). 

Therapeutic Uses. — Naphtalin and naphtol were at first introduced 
as external applications in parasitic skin diseases of various forms, but 
have been more extensively prescribed as intestinal disinfectants. In 
some disorders, such as diarrhoea, in which the walls of the intestine 
are only secondarily affected by the putrefaction of the contents, they 
have proved very efficacious, but when the intestinal walls themselves 
are the seat of the primary disease, as in typhoid fever and dysentery, 
they are of more doubtful value. They have been employed as an- 
thelmintics to a limited extent, and apparently with some success, 
though they have not proved so reliable as some of the older drugs 
used for this purpose. Naphtol is more largely used than naphtalin in 
internal medication, and may be prescribed as a powder or in capsules. 
They are used externally as ointments (5-10 per cent.). Naphtalene 
and naphtol ought to be avoided in irritation of the kidneys, bladder 
or urethra. 

Bibliography. 

Rossbach. Berl. klin. Woch., 1884, pp. 665, 729. 

Willenz. Therap. Monatsheft, 1888, p. 20. 

Neisser. Centralbl. f. med. Wiss., 1881, p. 545. 

Baatz. Centralbl. f. inn. Med., 1894, p. 857. 

Lesnik. Arch. f. exp. Path. u. Pharm., xxiv., p. 168. 

Bouchard u. Charrin. Therap. Monatsheft, 1887, p. 119. 

Kolinski. St. Petersburg med. Woch., 1889. 



410 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

Magnus. Therap. Monats., 1887, p. 387. 

Klingmann. Virchow's Arch., cxlix., p. 12. 

Manca and Ovio. Arch. Ital. de Biologie, xxxiv., p. 265. 

v. d. Hoeve. Arch. f. Ophthalmol., liii., p. 74. 



4. Tar. 

The action of the various crude preparations of the antiseptic series 
resembles that of the pure principles but as in most of them the creo- 
sols, guaiacols and other less poisonous aromatic compounds are present 
in larger quantity than the phenols and dioxybenzols, they are less 
poisonous than carbolic acid and its simpler homologues. At the same 
time these higher combinations do not seem to be much less antiseptic 
than the simpler benzol derivatives, so that several of the crude prepa- 
rations possess considerable value in surgery and medicine. 



Preparations. 

Pix Liquida (U. S. P., B. P.), tar, is obtained from the wood of Pinus 
palustris and other species of Pinus by destructive distillation and contains 
a very large number of aromatic bodies mixed with others of less importance. 
Oleum Picis Liquids? (U. S. P.), oil of tar, is a volatile oil distilled from 
tar, and is similar to creosote, except that it consists almost entirely of 
guaiacols and their compounds. 0.05-0.3 c.c. (1-5 mins.). 

Syrupus Picis Liquids (U. S. P.), syrup of tar, 4-12 c.c. (1-3 fl. drs.). 

Unguentum Picis Liquidae (U. S. P., B. P.). 

Pix Carbonis Prseparata (B. P.), prepared coal-tar. 

Liquor Picis Carbonis (B. P.), a solution of coal-tar in tincture of Quil- 
laia bark. 

Oleum Cadinum (U. S. P., B. P.), oil of cade or empyreumatic oil of juniper. 
Juniper tar oil is the tar distilled from the juniper, and contains dioxybenzol 
and guaiacol combinations. It is less strongly disinfectant than the other 
tars. 

Tar is a valuable disinfectant, which is very generally available and 
is much cheaper than the purer bodies of the aromatic series. It may 
be used for the disinfection of excrementa, latrines, etc., where the cost 
of even crude carbolic acid would be prohibitive. 

Tar has also been used with considerable success as an antiseptic in 
skin diseases, in which it may be applied either alone or as an oint- 
ment. It is only slightly irritating to the skin, and some absorption 
occurs, as is often seen by the dark color of the urine. Internally it 
has been used occasionally as an anthelmintic and intestinal disinfec- 
tant, much more frequently as an " expectorant " in cough mixtures. 
Whether it has any effects on the lungs or not in these cases may be 
questioned. It is generally given as the syrup, sometimes as tar water. 



Bibliography. 

Nencki u. Sieber. Arch. f. exp. Path. u. Pharm., xxxiii., p. 1. 
Strom. Arch. d. Pharmacie, ccxxxvii., p. 525. 



ANTISEPTICS OF THE AROMATIC SERIES. 411 



• 



Creosote. 

Creosote may be regarded as a wood-tar from which the more 
poisonous phenols and the less volatile bodies have been eliminated, 
leaving guaiacols and creosols as the chief constituents. Its action 
is similar to that of carbolic acid, except that it has less tendency to 
induce nervous symptoms, and is less irritant and poisonous. On the 
other hand, it seems at least as strongly antiseptic as carbolic acid, and 
according to some investigators, far excels it as a germicide. 

Peepaeations. 

Creosotum (U. S. P., B. P.) is obtained from wood-tar, preferably from 
beech tar, and is an almost colorless oily liquid with a smoky odor and hot, 
burning acrid taste. It is slightly soluble in water, but mixes readily with 
alcohol. It tends to darken in color when exposed to the light. 0.05-0.3 
c.c. (1-5 mins.). 

Aqua Creosoti (IT. S. P.), a very dilute solution of creosote in water, less 
than one per cent. 2-8 c.c. (J-2 £L. drs.). 

Mistura Creosoti (B. P.) containing spirits of juniper, J-l fl. oz. 

Unguentum Creosoti (B. P.). 

Creosote may be administered in pills, capsules, in solution in alcohol or 
cod-liver oil, or as a mixture (B. P.). The wine of creosote, which has been 
a popular remedy, contains it dissolved in wine along with some brandy 
and tincture of gentian. It ought not be allowed to reach the mucous 
membranes in a concentrated form, as it is liable to irritate them. 

Therapeutic Uses. — Creosote is comparatively seldom used except 
in the treatment of pulmonary phthisis and gangrene, and chronic 
bronchial inflammation. It is generally given by the mouth in these 
cases, but has also been injected hypodermically or into the rectum ; the 
vapor is recommended as an inhalation, and some practitioners have 
injected creosote solution into the trachea, in order to ensure its reach- 
ing the lungs. None of these methods are believed to give such good 
results as the ordinary administration by the mouth. 

The results of creosote medication are still disputed. Many clin- 
icians state that a general improvement follows it in phthisical pa- 
tients, that the appetite is improved, the cough and expectoration les- 
sened, and that the patient feels stronger and better. On the other 
hand, others are extremely sceptical as to any benefits arising from 
creosote, and regard it as merely one of the countless remedies which 
have been recommended in this condition, and which after a shorter 
or longer period of popularity have passed into oblivion. 

It is generally supposed by the advocates of the creosote treatment 
that the remedy destroys the tubercle bacillus in the lungs through its 
antiseptic properties. On the other hand, animals infected with tubercle 
and treated with creosote die as soon as controls which are untreated, 
and the sputum of phthisical patients treated with creosote is as viru- 
lent as that of others not so treated. Besides, the administration of 
creosote by other ways than by the mouth is said to be very much less 
efficacious. Another explanation of the creosote action is that it acts 



412 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

as an intestinal antiseptic and prevents the secondary infection of the 
bowel ; but it has been objected to this that the other intestinal anti- 
septics are of little value in tuberculosis. It seems useless to specu- 
late on the method of action until it has been definitely determined 
that creosote is of value in phthisis, and this can be done only by 
careful statistical inquiry. The medical profession seems to have much 
less faith in the efficacy of the creosote treatment than it had a few 
years ago, when it was not generally recognized that pulmonary tuber- 
culosis is curable by hygienic measures in a considerable proportion of 
instances. 

Creosol, an ether of dioxytoluol, is contained in creosote and other wood- 
tar, and has, as far as is known, effects similar to those of the allied bodies, 
but has not been investigated so carefully as some of the others. 

Guaiacol, the methyl ether of pyrocatechin, seems to be somewhat more 
poisonous than carbolic acid according to Marfori, whose preparations, 
however, were by no means pure. The symptoms induced were those 
characteristic of the series, but it is desirable that the toxicity of guaiacol 
should be ascertained more accurately, as it forms an important ingredient 
of tars and other crude remedies. 

Guaiacol Carbonate seems to have the same effects as guaiacol, as far as 
they have been investigated. 

It was found a few years ago that guaiacol applied to the skin over a 
sufficiently wide area produced a marked fall of temperature in fever, but 
this does not seem to be any specific effect of guaiacol, and would probably 
have resulted from the application of any other equally volatile member 
of the group. The explanation is that a certain proportion of the guaiacol 
applied is absorbed from the skin, and the fall of temperature is one of the 
symptoms of poisoning. Considerable quantities of guaiacol have been re- 
covered from the urine after this method of medication. At the same time, 
it is probable that the irritation of the skin may also produce an alteration 
of the output of heat through a reflex effect on the vaso-motor centres. 
The fall of temperature is generally abrupt and is accompanied by some 
exhaustion and weakness, and by profuse perspiration. The temperature 
soon rises again to its former height with shivering and rigors, and there 
seems good reason, therefore, why guaiacol should not be classed among the 
more satisfactory antipyretics. 

Guaiacol has been administered as a substitute for creosote in tubercular 
disease. It is generally given in solution in alcohol or cod-liver oil, or in 
pills. Dose, 0.05-0.2 G. (1-3 grs.). It has also been injected hypodermi- 
cally, but has not had such good results. 



Xchthyol. 

Ichthyol, thiol, and similar bodies possess some antiseptic action, although 
they are believed to be less powerful than carbolic acid. Applied to the skin, 
ichthyol causes slight irritation, which is apparently of benefit in some cu- 
taneous diseases, and it has therefore been used extensively for this action. 
It is said to cause marked contraction of the vessels when it is applied 
locally, but this requires confirmation. A certain amount of absorption oc- 
curs when it is rubbed into the skin, for the sulphur of the urine has been 
found to be augmented. Taken internally in large quantities, it acts as a 
gastric and intestinal irritant and produces diarrhoea, but it is only very 
feebly poisonous. It has been said to lessen to a marked extent the nitro- 
genous metabolism, but this seems incorrect, for Helmers found only a very 



ANTISEPTICS OF THE AROMATIC SERIES. 413 

slight and inconstant fall in the nitrogen of the urine in man. It is ex- 
creted in the urine and probably by the intestinal wall. 

Ichthyol has been strongly recommended in the treatment of a number of 
skin diseases, including erysipelas. It is generally used as an ointment con- 
taining equal parts of ichthyol and of vaseline, but may be used in ten 
per cent, or even weaker dilution. It has also been advised as an applica- 
tion over inflamed and rheumatic joints, indurated glands and swellings, and 
chronic inflammations of the pelvic viscera, and is said to cause the absorp- 
tion of the products of inflammation. Its effects can be explained in 
these cases only by the slight irritant action on the skin. It has been 
given internally in pills or capsules in doses of 0.2-0.5 G. (3-8 grs.) in cases 
of rheumatism, erysipelas, and in many chronic diseases, but seems of very 
doubtful benefit. In fact, ichthyol has in the last few years been enthusastic- 
ally praised as a remedy in the most diverse conditions, and it seems prob- 
able that its sphere of utility will be very much more restricted in the future, 
if it does not disappear from therapeutics entirely. 

Bibliography. 

R. Abel. Centralbl. f. Bacteriologie, xiv., p. 413. 
Zuelzer. Monatsh. f. prakt. Dermatologie, 1886, p. 547. 
Helmers. Virchow's Arch., cxxxv., p. 135. 

5. Salicylic Acid. 

Salicylic acid differs from phenol chiefly in being very much less 
poisonous to the higher animals, while it is practically of equal an- 
tiseptic value, provided the conditions are favorable. The salicylates 
produce the same effects as the free acid, excepting that they are 
much less irritant to the skin and mucous membranes. It was for- 
merly stated that the salicylate of soda, which is the only salt that has 
been largely used, was devoid of antiseptic action, but this has been 
shown to be incorrect. 

Antiseptic Action. — Salicylic acid retards the digestion of proteids 
by the gastric and pancreatic juices, and the decomposition of gluco- 
sides by the unorganized ferments, but how far this effect is due to the 
free acid, and how far to a specific antiferment-action, cannot be defi- 
nitely stated. The putrefaction of proteid solutions, and the alcoholic 
and acetic acid fermentations are also retarded, or entirely prevented 
by the presence of comparatively small quantities of salicylic acid or of 
the salicylates. They offer some points of contrast with carbolic acid, 
however, for it is found that if much proteid be present the salicylic 
preparations are generally less efficient than phenol ; this is perhaps 
due to the phenol being volatile and therefore penetrating more readily 
and forming less stable combinations with the proteid. Salicylic acid 
on the other hand does not evaporate, and therefore preserves bodies 
which are exposed to the air for a longer time than carbolic acid, 
which is soon dissipated. These considerations may perhaps explain 
the very different results which have been obtained by different ob- 
servers in regard to the comparative germicidal power of these sub- 
stances. The movements of plant protoplasm, protozoa and leucocytes 
are prevented by salicylic acid as by quinine and the other aromatic 
antiseptics. 



414 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

Irritant Action. — Salicylic acid is much less irritant than phenol, 
but when it is applied for some time as a powder to wounds, mucous 
membranes, or even the skin, it may induce the same corrosion and 
necrosis as have been mentioned under carbolic acid. In solution it 
has a destructive action on the horny layer of the epidermis, which be- 
comes softened and easily removed, without any noticeable irritation 
having been induced. It sometimes causes soreness and irritation of 
the mouth and throat when swallowed in powder, and congestion and 
even erosion of the mucous membrane of the stomach have been ob- 
served. In dilute solution, however, the acid has no such effect, and 
even comparatively concentrated solutions of the salts seem almost 
devoid of corrosive properties. 

Symptoms. — Salicylic acid and its salts are rapidly absorbed from 
the stomach and intestine, and as a general rule produce no symptoms, 
unless when given in very large doses. Some individuals, however, 
are peculiarly sensitive to the action of salicylic acid, and in these, 
comparatively small doses are followed by symptoms which are gen- 
erally of only slight importance, but which are sometimes sufficiently 
grave to cause anxiety, and in very rare cases have been followed by 
death. 

The ordinary symptoms are a feeling of heaviness and fulness in the 
head, with hissing or roaring sounds in the ears exactly resembling 
those produced by quinine. These may be followed by some confusion 
and dulness, and by indistinct sight and hearing. Very often the 
patient complains of excessive perspiration and a sense of warmth all 
over the body. Dyspnoea, marked by exceedingly deep and labored 
respiration, has been noted in more serious cases of poisoning, and a 
condition of collapse with slow weak pulse, subnormal temperature, 
and partial or complete unconsciousness may follow. In others, de- 
lirium and hallucinations of sight and hearing have occurred, these 
being more frequently seen in chronic alcoholic patients and in cases 
of diabetes than under other conditions. Albumin and even haemo- 
globin and blood in the urine have also been noted as sequelae. Vari- 
ous forms of skin eruptions have been described as occurring under the 
use of salicylic acid, sometimes after a single dose, but much more 
frequently after prolonged treatment. They resemble those seen under 
the antipyretics, but seem to be less frequently elicited by salicylic 
acid. Abortion has been repeatedly observed under salicylate treat- 
ment, but, as in the case of quinine, it seems open to question whether 
this was due to the remedy or to the disease. Haemorrhages from the 
uterus, nose, mouth and intestine have also been credited to the action 
of this drug, and, in fact, nose-bleeding has been said to occur in a 
considerable proportion of the cases treated with it. Numerous other 
symptoms have been noted after salicylic acid, but so rarely that a 
doubt may be entertained as to whether they were not due to some 
special condition, or perhaps to some impurity in the drug. 

In animals, salicylic acid injected intravenously causes some acceler- 
ation of the pulse and respiration, followed by slowness and weakness 



ANTISEPTICS OF THE AROMATIC SERIES. 415 

of the heart, and often by marked dyspnoea. Depression of the central 
nervous system is shown by slowness, weakness and incoordination of 
the spontaneous movements, and eventually by stupor and arrest of 
the respiration, which is generally preceded by convulsions. Photo- 
phobia and clonic spasms have been observed in some dogs. Hyper- 
emia of the kidney, liver, brain and tympanum are sometimes found at 
the autopsy on dogs poisoned with salicylic acid, and when the drug 
has been given in powder, congestion, irritation and necrosis of the 
gastric mucous membrane. This irritation of the stomach often 
causes vomiting in dogs, and the poison being thus eliminated, no 
further symptoms appear. 

In the frog, salicylic acid produces quickened respiration and in- 
creased reflexes, followed by depression of the spontaneous movements, 
tremor and clonic contractions. The heart is slow, dilated and weak. 

The symptoms elicited by salicylic acid and its salts are therefore 
very indefinite, and with few exceptions occur so seldom in man that 
they may be discussed very shortly. 

The Disorders of Hearing have been shown, as in quinine, to be 
due to congestion of the tympanum, sometimes with ecchymoses and 
perhaps inflammatory reaction. As a general rule they pass off in the 
course of a few hours or days, but they sometimes leave a more or less 
permanent impairment of the sense of hearing. The Dimness of Sight, 
sometimes amounting to complete blindness, may perhaps be due to a 
constriction of the vessels of the eye (see quinine), and some disturbance 
of the circulation of the brain and head may be the cause of the dulness 
and fulness of the head complained of, and of the not infrequent 
epistaxis. Maragliano showed by plethysmography measurements 
that the Vessels of the Skin are dilated by salicylic acid in the same 
way as by the antipyretics. The exact mechanism by which these 
alterations in the distribution of the blood are produced is unknown, 
but the most probable explanation would seem to be that the vaso- 
dilator centres in the medulla controlling these areas are excited. 

The general Blood-Pressure is found to be increased by small quan- 
tities of the salicylates from stimulation of the vaso-constrictor centre, 
while after very large injections into the blood vessels, the pressure is 
lowered, partly perhaps from depression of the centre, but mainly from 
the cardiac action of the drug. 

Small quantities are found to accelerate the Heart in animals in the 
same way as small doses of the other aromatic bodies, apparently from 
direct action on the cardiac muscle. Very large doses produce a slow, 
weak, and dilated heart, and a corresponding fall in the blood-pressure. 

The acceleration of the Respiration and the dyspnoea, which have 
been noted occasionally in man, seem to be due to some central action. 
In animals the respiration is first accelerated to some extent, and then 
slowed, and some observers have attributed the acceleration to irrita- 
tion of the endings of the pneumogastric nerves in the lungs, without, 
however, bringing forward any satisfactory evidence in support of this 
explanation. It is more probable that the respiratory centre is first 



416 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

excited and then depressed, and eventually paralyzed by very large 
quantities of the drug. Death seems to be due to this paralysis, the 
heart continuing to beat for some time afterwards. 

The effects of salicylic acid on the Central Nervous System seem to 
be comparatively slight, except in cases in which a special idiosyncrasy 
exists. No such convulsive action as occurs under others of the aro- 
matic series has been observed under it, and in animals there seems no 
marked depression save in the medulla oblongata. The convulsions 
which are observed before death, are probably not due to the direct 
action of the drug, but to the asphyxia. In the medulla oblongata the 
respiratory and vaso-constrictor centres, and probably the vaso-dilator, 
seem to be first stimulated and then depressed. In the frog depres- 
sion and paralysis of the spinal cord are produced by large doses. 

The Perspiration which so often follows the administration of sali- 
cylic preparations, may be due in part to the dilation of the skin ves- 
sels, but is probably to be ascribed rather to increased activity of the 
sweat centres. Some of the Skin Rashes may also be caused by the 
dilation of the cutaneous vessels, and perhaps in all cases this may be 
looked upon as a favorable condition, which leads to eruptions in indi- 
viduals who are predisposed to them. 

The peripheral Muscles and Nerves do not seem to be more affected 
by salicylic acid than by the other members of the series. 

Salicylic acid and its salts increase to some extent the Secretion of 
the Urine, probably through a direct action on the renal epithelium, 
although the increased formation of urea may also play a part in the 
slight diuresis. Irritation of the kidney and nephritis are observed 
in some cases, with the appearance of albumin and blood in the urine. 

The salicylic preparations produce a slightly augmented flow of 
Bile, apparently from some specific action on the liver cells. The 
increase is so small, however, that some doubt is expressed by most 
writers on the subject. Pfaff found that in one case of biliary fistula 
in man the concentration of the bile was also increased, the solids 
being augmented in greater proportion than the fluid. 

Salicylates have been said to lower the normal Temperature, but 
this seems to be erroneous, except when very large quantities produce 
a condition akin to collapse. Some of the results may also be due to 
the use of impure preparations. In fever patients, however, it often 
causes a marked fall of temperature, and it was formerly used as an 
antipyretic for this reason. The action is probably explained by the 
dilation of the cutaneous vessels and the increase in the output of heat. 
(See Antipyretics.) Dilation of the skin vessels also occurs in normal 
persons after salicylates, but this is probably counterbalanced in them 
by increased heat formation. The fall in temperature after salicylic 
acid is generally less in extent and of shorter duration, than that fol- 
lowing the members of the antipyrine series. 

In its passage through the tissues, salicylic acid modifies the Meta- 
bolism, as is shown by an increase of 10-12 per cent, in the nitrogen 
and sulphur of the urine. This indicates a considerably augmented 



ANTISEPTICS OF THE AROMATIC SERIES. 417 

decomposition of the proteicls of the body, but whether it is accom- 
panied by increased oxidation is unknown. A still more notable 
augmentation of the uric acid excreted has been observed, different 
authors estimating it at 30-45 and even 100 per cent. The number 
of leucocytes in the blood has been found to undergo a corresponding 
increase. 

The form in which salicylic acid circulates in the blood was for- 
merlv the subject of some discussion, owing to the erroneous belief that 
its salts were devoid of antiseptic action. It is now known to exist 
in the blood as the salicylates of the alkalies. Gaglio states that it is 
taken up from the blood by the synovial membranes and rapidly ex- 
creted into the cavities of the joints, and is thus capable of exercising 
a specific action in acute rheumatism. It is Excreted by the kidneys, 
for the most part in a combination with glycocoll, which is known as 
salicyluric acid, and which is strictly analogous to hippuric acid. 
Some of the salicylic acid is excreted uncombined. 1 It has also been 
found in the milk, perspiration and bile, but does not appear to be ex- 
creted into the stomach. 

Several compounds which owe their virtues to the salicylic acid 
radicle are used in medicine, and all produce similar results after ab- 
sorption, but vary in their local action. Methyl Salicylic Ester, which 
occurs in many plants and forms some 90 per cent, of the oil of winter- 
green, and almost the whole of the volatile oil of birch, has a hot, 
burning taste, and like other volatile oils produces a feeling of warmth 
in the stomach. In many cases it is well borne, but some patients 
complain of pain in the stomach, loss of appetite and even nausea and 
vomiting. It is rapidly absorbed and produces the characteristic 
symptoms of salicylic acid in large doses, roaring sounds in the ears 
and more or less deafness. It is partly excreted as salicyluric acid, 
the decomposition probably occurring mainly in the intestine. 

Salol, the phenyl salicylic ester, is a very insoluble, crystalline body, 
which has little or no local action in the mouth or stomach, but is de- 
composed in the intestine by the fat-splitting ferment of the pancreatic 
juice. Some decomposition also appears to occur in the stomach, at 
any rate under certain conditions. The products of its decomposition, 
salicylic and carbolic acids, are absorbed and produce their usual 
effects. Salol is used chiefly as a substitute for salicylic acid, but the 
formation of phenol from it in the body must not be overlooked, for in 
several cases of dangerous poisoning which have been observed under 
it, the symptoms were those characteristic of carbolic acid, and the urine 
became dark in color from the phenol oxidation products. In moderate 
quantities, salol produces the disturbances of hearing observed under 
salicylic acid, without any symptoms of carbolic poisoning. 

Other salicylic acid compounds, similar to salol, are betol or napktcUol 
(the beta-naphtol salicylate), crescdol (cresol and salicylic acid), thymo- 
mdol (from thymol), guaiaeolsalol, while salipheu, malakine, etc., have 

1 Lesnik is inclined to believe that some of the salicylic arid exists in the urine as a 
double molecule of the acid combined by means of a tartronie radicle. 
27 



418 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

been mentioned among the antipyretics. They are less poisonous than 
salol, and may be used for most purposes as substitutes for salicylic 
acid. Saliphen, malakine and their allies have a more powerful anti- 
pyretic action than salicylic acid. On the other hand, the salicylic 
esters, including methyl and phenyl salicylates, are less antiseptic than 
salicylic acid and its salts. 

Salicin, a glucoside found in many species of willow and poplar, is 
decomposed into salicylic alcohol, which is oxidized to salicylic acid in 
the body, so that its action after absorption is similar to that of the 
acid. It is unknown whether the decomposition occurs in the alimen- 
tary canal or in the tissues, but from the fact that it is excreted mainly 
as salicin when it is injected intravenously, it would seem probable 
that the decomposition, like that of the ordinary esters, takes place 
chiefly in the intestine. It is very bitter, but does not irritate the 
mucous membranes, and is not so certain in its action as salicylic acid 
and some of its esters. When administered by the mouth it is excreted 
in the urine partly as salicin, partly as saligenin or salicyl alcohol, and 
partly as salicylic and salicyluric acids. 

Preparations. 

Acidum Salicylicum (U. S. P., B. P.), salicylic acid (C 6 H 4 OHCOOH) 
small, white, needle-like crystals, or a light crystalline powder, odorless with 
a sweetish, afterwards acrid, burning taste, slightly soluble in water, very 
soluble in alcohol or ether. A reddish tinge indicates the presence of car- 
bolic acid or other impurities, and salicylic acid for internal use ought to be 
entirely colorless. 1 Salicylic acid is much more soluble in solutions of neu- 
tral salts, such as the borates or citrates, than in pure water. 0.3-2 G. (5-30 
grs.). It is generally given in capsules or tablets. 

Unguentum Acidi Salicylici (B. P.), 2 per cent. 

Sodii Salicylas (U. S. P., B. P.), sodium salicylate (C 6 H 4 OHCOONa), a 
white odorless powder with a sweetish taste, very soluble in water, less so 
in alcohol. 0.6-2 G. (10-30 grs.) in capsules or tablets, or dissolved in 
syrup. 

Lithii Salicylas (U. S. P.), 0.3-2 G. (5-30 grs.). 

Oleum Gaultherise (U. S. P.), oil of w T intergreen, a colorless or yellowish 
fluid with a characteristic, pleasant odor and a sweetish, aromatic taste, in- 
soluble in water, soluble in alcohol, contains 90 per cent, of methyl salicy- 
late. 0.3-1 c.c. (5-15 mins.) in emulsion or in capsules. 

Oleum Betulse Volatile (U. S. P.), oil of sweet birch. 

Methyl Salicylas (U. S. P.), artificial oil of wintergreen (C 6 H 4 OHCOOCH 3 ), 
is practically identical with the oil of sweet birch and forms 90 per cent, of 
the oil of wintergreen. It may be prescribed in the same doses and forms 
as the latter. 

Spiritus Gaultherise (IT. S. P.) is used as a flavor chiefly. 1 c.c. (15 mins.). 

Salicinum (II. S. P., B. P.), salicin (C 6 H n 5 OC 6 H 4 CH 2 OH), a glucoside 
obtained from several species of willow and poplar, consists of white, silky, 
crystalline needles, with a very bitter taste, soluble in 28 parts of water. It 
is decomposed by ferments into glucose and saligenin or salicyl alcohol 
(C 6 H 4 OHCH 2 OP0. 0.5-2 G. (8-30 grs.) or more every 3 or 4 hours, given 
in powder, capsules or in solution, which, however, is very bitter. 

Salicylic acid formed synthetically from phenol is often said to be more poisonous 
than that obtained from the oil of wintergreen (methyl salicylate), but this is due not 
to any difference in the acid, but to the presence of carbolic acid and other impurities 
in the artificial preparation. 



ANTISEPTICS OF THE AROMATIC SERIES. 419 

Salol (U. S. P., B. P.), phenyl salicylate (C 6 H 4 OHCOOC 6 H.), a white 
crystalline powder, odorless or faintly aromatic, almost tasteless, almost in- 
soluble in water, decomposed by the pancreatic juice into salicylic acid and 
phenol. 0.5-2 6. (5-30 grs.) in powder or capsule. 

Aspirin or acetylsalicylic acid, is very slightly soluble in water and has a 
more pleasant acid taste than salicylic acid but offers no further advantages 
over it. It is decomposed into salicylic acid in the intestine. Dose, 2-3 
G. (30-40 grs.). 

Therapeutic Uses. — Salicylic acid and the salicylate of soda were at 
one time used to a considerable extent as antiseptics in surgery, and in- 
deed promised to supplant carbolic acid for this purpose, as they were 
less irritating and also less poisonous. They have been less used of 
late years, and although bacteriological experiment has shown that the 
acid is at least as destructive to the pyogenic organisms as carbolic 
acid, most surgeons find it less satisfactory in practice. 1 

Salicylic acid is occasionally applied locally in excessive sweating, 
and has also been used in various skin affections in which it is desir- 
able to soften or partially dissolve the epidermis. Both acids and salts 
are absorbed too rapidly to act as intestinal disinfectants. 

In 1875 it was found to have antipyretic properties, and for a few 
years it was used as a general antipyretic in fever, but has been entirely 
supplanted for this purpose by the more recently discovered antipyrine 
series. It was also suggested as a substitute for quinine, but has no 
such specific action on the malarial organisms. 

The chief sphere of usefulness of salicylic acid at the present time 
is in the treatment of acute rheumatic fever, in which it seems to have 
a specific action only excelled by that of quinine in malaria. Other 
members of the aromatic series have some effect in this condition, but 
none of them equal the salicylic preparations in efficacy. Under this 
treatment the pain and swelling in the joints rapidly lessen, the tem- 
perature often falls, and the course of the disease is shortened. It is 
still debated whether the salicylic treatment reduces the liability to 
endocarditis and pericarditis, which are common complications of acute 
rheumatic fever ; some clinicians even state that it increases the risk 
of these complications, while others advise the discontinuance of the 
treatment when auy symptoms arise from the heart. The view more 
generally entertained, however, is that the cardiac affections are less 
often met with and are less severe under salicylic treatment, and very 
often it is continued in small quantities even after the heart is undoubt- 
edly involved in the disease. The remedy sometimes fails in rheuma- 
tism, as quinine does in malaria, and it sometimes acts more satisfac- 
torily in one joint than in another. Large doses (1-2 G. or 15-30 
grs.) repeated every 2-3 hours are necessary in some cases at first, the 
quantity being reduced as the symptoms abate. Salicylic acid is less 
frequently used than the salicylate of soda or salol, but some clinicians 

J Salicylic acid has been used very largely as a preservative in wine and beer. Xo 
evil effects have been definitely shown to follow the prolonged use of liquors thus 
treated, but it is not impossible that they may ho injurious, and several governim-nts 
have found it advisable to prohibit its use for this purpose. 



420 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

hold that the acid is the most efficient of the three. Oil of winter- 
green may also be used here, but, like salicylic acid, is more liable to 
cause gastric irritation. When high fever is present the antipyretic 
combinations of salicylic acid, such as malakine, may be used with 
advantage. Salicin is less disturbing to the stomach than the other 
preparations, but is less certain in its effects and has to be given in 
larger quantities. 

Salicylic acid has also been used in the various forms of disease 
which are roughly classified as rheumatic — chronic rheumatism, arth- 
ritis, neuralgia, myalgia — but the effects are less satisfactory than in 
acute rheumatism. The lithium salt is contained in the U. S. P. 
because lithium is erroneously credited with a special solvent action on 
the uric acid in these diseases. 

In other acute constitutional diseases accompanied by fever, salicylic 
acid is of less value than in acute rheumatism so that it would appear 
that it has a specific action on the unknown cause of this malady. 

Salicylic acid in some cases promotes the absorption of effusions into 
the serous membranes, such as the pleura, and also subretinal effusion. 
It is unknown how this is effected, but it scarcely seems probable that 
the slight diuretic action of the drug is sufficient to account for it. 

The cholagogue action of the salicylates is quite inconsiderable in 
comparison with that of the bile itself, and in any case in which an 
increase of the bile secretion is desirable, recourse should be had rather 
to the latter. (See Bile.) 

The solubility of the salicylates and their rapid absorption precludes 
their use as intestinal antiseptics, but salol has been used to lessen 
putrefaction in the bowel, and even to act upon the bacilli of typhoid 
fever and of tubercle infecting the intestinal wall. Kumagawa, how- 
ever, states that the putrefaction in the bowel as measured by the in- 
dican in the urine is unchanged by its administration, and he found 
enormous numbers of bacteria in the faeces afterwards. It certainly 
seems of little value in typhoid fever or in tuberculosis of the intes- 
tine. Intestinal calculi have been formed in a few instances from 
prolonged treatment with salol, which failed to be decomposed in the 
intestine and formed masses of considerable size. 

Salol was at one time supposed to be absorbed only after its de- 
composition in the intestine by the pancreatic juice, and Ewald there- 
fore suggested its use as a means of diagnosing stenosis of the pylorus. 
He supposed that in cases in which the food was delayed or prevented 
from passing into the intestine, the reaction of salicylic acid in the 
urine would appear correspondingly late or be entirely absent. But 
some salol seems to be absorbed from the stomach, and, on the other 
hand, the interval between its administration and the appearance of the 
salicylic reaction in the urine is so variable in normal individuals 
that the test is of little value. Salol has been used to coat pills and 
prevent their solution in the stomach. 

Salol has some value as a geni to- urinary disinfectant, partly owing 
to the salicylic acid component and partly to the phenol developed. 



ANTISEPTICS OF THE ABO MA TIC SERIES. 421 

It is used as a substitute for salicylic acid in rheumatic fever, as has 
been mentioned, and has the advantage of being tasteless and of pro- 
ducing no irritation in the stomach. On the other hand, the consid- 
erable amount of carbolic acid freed by its decomposition has given 
rise to poisoning in some cases. Externally it is of little or no value 
as an antiseptic, as it is only active when decomposed by the microbes 
which it is designed to destroy. 

Salicin is used as a substitute for salicylic acid only in rheumatic 
fever. It has been prescribed as a stomachic bitter. 

Salicylic preparations have to be used with care where any symp- 
toms of renal irritation are present. In cases of poisoning, the treat- 
ment is determined entirely by the symptoms, and no antidote is 
known. Glycocoll has been suggested for the same reason as the sul- 
phates in phenol poisoning, but would presumably be of no greater 
value. 

Bibliography. 

Kolbe. Journ. f. pract. Chemie, x., p. 89; xi., p. 9 ; xii., p. 161. 
Neubauer. Ibid., xi., p. 1. 
Schaer. Ibid., xii., p. 123. 
Mayer u. Kolbe. Ibid., xii., pp. 133 and 178. 
Laborde. Bull, de Therap., xciii., p. 276. 
Quincke. Berl. klin. Woch., 1882, p. 709. 

Charteris and McLennan. Brit. Med. Journ., 1889, ii., p. 1208. 
Bauer u. Kiinstle. Deutsch. Arch. f. klin. Med., xxiv., p. 53. 
Wolfsohn. Inaug. Diss., Konigsberg, 1878. 
Sassetzky. Virchow's Arch., xciv., p. 485. 
Kohler. Central, f. d. med. Wissen., 1876, p. 161. 
Lymas. Inaug. Diss., Erlangen, 1876. 
Huber. Deutsch. Arch. f. klin. Med., xii., p. 129. 
Kirchner. Berl. klin. Woch., 1881, p. 725. 
Maragliano. Zts. f. klin. Med., xvii., p. 291, and xiv., p. 309. 
Gottlieb. Arch. f. exp. Path., xxvi., p. 436. 
Kwmagawa. Virchow's Arch., cxiii., p. 134. 
Baumann. Zts. f. phys. Chem., i., p. 253. 

Binz. Arch. f. exp. Path. u. Pharm., vii., p. 280, and x., p. 147. 
Feser u. Friedbarger. Arch. f. wissens. u. practische Thierheilkunde, 1875. 
Bohland. Centralb. f. inn. Med., xvii., p. 70. 
Nencki. Arch. f. exp. Path. u. Pharm., xxxvi., p. 401. 
Bucholtz. Ibid., iv., p. 1. 

Bochefontaine. Comptes rendus d. 1. Soc. de Biol., 1884, p. 412. Comptes rendus 
de 1' Academie, lxxxv., p. 574; lxxxvii., p. 657. 

Mosso. Arch. f. exp. Path. u. Pharm., xxvi., p. 267. 

C. Virchow. Zts. f. physiol. Chem., vi., p. 78. 

Bass. Deutsch. Arch. f. klin. Med., xv., p. 457. 

Buchmann. Inaug. Diss., Kiel, 1892. 

Baelz. Arch. d. Heilkunde, xviii., p. 60. 

Pfaff. Jour, of Exp. Med., ii., p. 49. 

Gaglio. Arch. Ital. de Biol., xxxi., p. 304. 

Schreiber u. Zandy. Deutsch. Arch. f. klin. Med., lxii., p. 242. 

Goodbody. Journ. of Physiol., xxv., p. 399. 

Ulrici. Arch. f. exp. Path. u. Pharm., xlvi., p. 321. 

Salol. 

Nencki. Arch. f. exp. Path. u. Pharm., xx., p. 367. 

Lesnik. Ibid., xxiv., p. 167. 

Hesselbach. Practitioner, xlv., p. 12. 

Sahli. Therap. Monats., 1887, p. 333. 

Ewald u. Sievers. Ibid., p. 289. 

Marshall. Brit. Med. Journ., 1897, ii., p. 78. 



422 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

Betol. 

Robert Therap. Monats., 1887, p. 164; 1888, p. 220. 
Sahll. Ibid., 1887, p. 212. 

Salicin. 

Marme. Gottingen. Nachricht., 1878, p. 229. 
Maclagan. Lancet, 1876, i., p. 342. 
Senator. Berl. klin. Woch., 1877, p. 181. 

Aspirin. 

Dreser. Pfl tiger's Archiv, lxxvi., p. 306. 

Singer. Ibid., lxxxiv., p. 527. 

Gazert. Deutsch. Arch. f. klin. Med., lxviii., p. 142. 

Other Aromatic Oxy- acids. 

The two isomers of salicylic acid, meta- and para-oxybenzoic acid, are said to 
be almost devoid of antiseptic properties, and, although some doubt may be 
entertained as to the correctness of this statement, they have never been used 
in medicine except experimentally. 

The cresotinic acids resemble salicylic acid in their effects, and the para- 
cresotinate of soda has been used occasionally as an antipyretic and substi- 
tute for salicylic acid. The metacresotinate is very much less active, while 
the orthocresotinate possesses a dangerous action on the heart. The para- 
cresotinate is somewhat less poisonous than salicylic acid. The cresotonic 
acids are found as impurities in some commercial specimens of salicylic acid, 
but these ought not to be used for internal administration, as the presence of 
the orthocresotonic acid may affect the heart. 

The alpha- and beta-oxynaphtoic acids are possessed of antiseptic proper- 
ties, which are said to be somewhat greater than those of carbolic and sali- 
cylic acids, but they are less soluble in water, while the sodium salt is less 
antiseptic. The acids are irritant and produce diarrhoea and symptoms 
similar to those of salicylic acid. They seem to be at least as poisonous as 
carbolic acid, and have been used as external antiseptics only to a very 
limited extent. 

BlBLIOGKAPHY. 

Buss. Berl. klin. Woch., 1876, p. 445. 

Demme. Therap. Monats., 1890, p. 191. 

Henne. Inaug. Diss., Bern, 1890. 

Charteris. Brit. Med. Journ., 1891, i., p. 695. 

Ellenberger u. Hofmeister. Arch. f. exp. Path. u. Pharm., xxiv., p. 261. 

Willenz. Therap. Monatsheft, 1888, p. 20. 

Sulphocarbolates. 

The sulphon group lessens the toxicity in the same way as carboxyl, and 
the sulphocarbolates or para-phenol-sulphonates are therefore less poisonous 
than carbolic acid. The sulphocarbolates of sodium and zinc have been used 
as external antiseptics, and the sulphocarbolate of sodium has been adminis- 
tered to arrest fermentation in the stomach. The zinc salt possesses some 
astringent action and has been used with good results as an injection in gon- 
orrhoea. The sodium salt is probably excreted in the urine unchanged. 
Aseptol or sozolic acid is a 33 per cent, solution of orthophenol-sulphonic 
acid in water but very often contains some of the para-acid. 

Sodii Sulphocarbolas (U. S. P., B. P.), or sodium para-phenol-sulphonate 
(C 6 H 4 OHS0 2 ONa, 2H 2 0), forms colorless, transparent prisms, without odor, 
and with a saline taste. Soluble in 5 parts of water. 0.3-1 G. (5-15 grs.). 

Zinci Sulphocarbolas (B. P.), (Zn(OHC 6 H 4 S0 3 ) 2 H 2 0) forms colorless, trans- 
parent, efflorescent crystals, which are very soluble in water and in alcohol. 



ANTISEPTICS OF THE AROMATIC SERIES. 423 

Bibliography. 

Servant. Comptes rendus de l'Academ., c, pp. 1465 and 1544. 
Hueppe. Berl. klin. Woch., 1886, p. 609. 
Samter. Inaug. Diss., Berlin, 1887. 

Benzoic Acid. 

Benzoic acid possesses almost the same action as salicylic acid in 
the body, and like it, is poisonous only in comparatively large quanti- 
ties. It seems to be equally, or according to some observers, more 
strongly antiseptic, and like salicylic acid irritates the mucous mem- 
branes, while its salts are practically devoid of this last property. 
Benzoic acid is, however, apparently less stimulant to the central 
nervous system, and the characteristic affections of the hearing and 
sight have not been observed under it. 

In man, very large quantities of benzoic acid and also of the ben- 
zoate of soda sometimes produce nausea and vomiting, the vomited 
matter rarely being tinged with blood. A certain sedative action on 
the central nervous system is also said to be observed, and an increased 
expectoration of mucus is produced in cases of bronchial irritation. 
The pulse is somewhat accelerated. 

In the dog, tremors and convulsions have been observed, but are 
generally less marked than under carbolic acid. Ataxia, paresis, and 
eventually complete paralysis of the fore limbs, and later of the hind 
limbs and trunk follow, the temperature falls, and death occurs from 
asphyxia. The heart and respiration are first accelerated and then 
slowed, from a direct action on the heart and on the respiratory centre. 
Vomiting occurs when the acid or the salts are given by the mouth. 
Post-mortem the gastric mucous membrane has been found to be 
eroded and ecchymosed, even when the salts or acid have been injected 
subcutaneously or intravenously, so that the benzoates and benzoic 
acid would seem to have a specific action on the gastric mucous mem- 
brane quite apart from their irritant effects when applied locally. 

In frogs, fibrillary contractions and convulsions are observed, followed 
by weakness and paralysis of the spinal cord. Haemorrhages have 
also been found in the stomach when the drug was injected into a 
lymph-sac. 

Benzoic acid (C 6 H.COOH) combines with glycocoll in the body to 
form hippuric acid (C 6 H 5 CO — NHCH 2 COOH), which is excreted in 
the urine. Some of the benzoic acid escapes in the urine unchanged, 
however, the proportion of hippuric acid formed apparently varying 
with the general health and the condition of the kidneys, and also with 
the dose administered. After large doses a reducing body has been 
observed in the urine, presumably glycuronic acid. Traces of benzoic 
acid are found in the saliva of the dog after its administration, but it 
does not seem to be excreted here in man. In birds, benzoic acid is 
excreted by the kidneys as ornithuric acid (C 10 H, () N,O 4 ), from which 
benzoic acid can be split off, leaving ornithin. Benzoic acid often in- 
creases the nitrogen eliminated in the urine, so that in these cases it 



424 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

augments the decomposition of the proteids like salicylic acid ; in 
other investigations no material change has been observed. It dif- 
fers from salicylic acid in its effect on the uric acid excretion, which 
is much reduced under benzoate treatment. 

Some diminution in the double sulphates and the indican of the 
urine have been observed after the administration of benzoic acid by 
the mouth, so that it apparently lessens the putrefaction in the in- 
testine. 

Cinnamic acid (C 6 H 5 — CH=CH— COOH) seems to resemble ben- 
zoic acid in its pharmacological characters, but has not been so care- 
fully examined. It increases the leucocytes of the blood and the uric 
acid of the urine to a marked degree. 

Preparations. 

Acidum Benzoicum (U. S. P., B. P.) (C 6 H 5 COOH), benzoic acid or flowers 
of benzoin, is prepared from benzoin by sublimation, or from toluol, and 
consists of white, feathery crystals, almost odorless, with a warm acid 
taste, very insoluble in water, soluble in alcohol, ether, fixed and volatile 
oils and in alkaline solutions. 0.3-1 G. (8-15 grs.), in powder or pill. 

Trochiscus Acidi Benzoici (B. P.), each contains £ gr. 

Sodii Benzoas (U. S. P., B. P.), easily soluble in water. 0.3-2 G. (5-30 
grs.), in solution. 

Lithii Benzoas (IT. S. P.), 0.3-2 G. (5-30 grs.). 

Ammonii Benzoas (IT. S. P., B. P.), 0.3-2 G. (5-30 grs.). 

Benzoic acid is also contained in paregoric. 

The Balsams are mixtures of resin, volatile oils, benzoic and cinnamic 
acids and their esters and small quantities of other aromatic bodies. 

Benzoinum (IT. S. P., B. P.), benzoin, a balsam obtained from Styrax Ben- 
zoin and probably from other species, varies in its composition with its place 
of origin, but contains much less cinnamic acid than the other balsams. 

Styrax (IT. S. P.), Styrax Prseparatus (B. P.), or storax, a balsam prepared 
from the inner bark of Liquidambar orientalis, contains resins, cinnamic 
acid and its esters. 

Tinctura Benzoini (IT. S. P.), 2-4 c.c. (30-60 mins.). 

Tinctura Benzoini Composita (IT. S. P., B. P.) contains, in addition to 
benzoin, storax, aloes and balsam of Tolu, and w T as formerly known as Bal- 
samum Traumaticum. A number of old remedies resembled it in composi- 
tion, such as Friar's balsam, Turlington's balsam, Jesuits' drops, etc. 2-8 
c.c. (30 mins.-2 fl. drs.). 

Balsamum Pertjvianum (IT. S. P., B. P.), Balsam of Peru, a balsam ob- 
tained from Toluifera Pereirse (IT. S. P.), or Myroxylon Pereirse (B. P.), con- 
tains cinnamic and benzoic acids (traces) and their esters, and resins. Ap- 
plied externally, either alone or in alcoholic solution. 0.3-1 c.c. (5-15 
mins.). 

Balsamum Tolutanum (IT. S. P., B. P\), Balsam of Tolu, a balsam obtained 
from Toluifera Balsamum or Myroxylon Toluifera, resembles balsam of Peru 
in composition, but contains more benzoic acid. 0.3-1 G. (5-15 grs.). 

Syrupus Tolutanus (IT. S. P., B. P.), 2-4 c.c. (£-1 fl. dr.). 

Tinctura Tolutana (IT. S. P., B. P.), 1-4 c.c. (15-60 mins.). 

Therapeutic Uses. — Benzoic acid and its sodium salt have been sug- 
gested as antiseptics and seem to be quite as satisfactory as salicylic 
acid, but have never been widely employed. Benzoin and the balsam 
of Peru are used extensively in parasitic skin diseases, especially in 



ANTISEPTICS OF THE AROMATIC SERIES. 425 

scabies. Internally the benzoates have been employed as substitutes 
for salicylic acid in acute rheumatism, but have not proved so efficient 
in general. The lessened putrefaction in the bowel after benzoic acid 
suggests its use as an intestinal disinfectant, and it has been adminis- 
tered as an antiseptic and slight irritant in diseases of the genito-uri- 
nary tract, such as cystitis and gonorrhoea. It was formerly supposed 
that benzoic acid lessened the uric acid excretion and dissolved the uric 
acid deposits in the bladder and tissues by forming hippuric acid, but 
this is now recognized to be erroneous, and the treatment of gout and 
other diseases based on this theory may be considered obsolete. The 
lithium benzoate of the U. S. P. is a survival of this treatment, lithium 
being credited with special solvent properties. 

Benzoic acid is still used as an ingredient in expectorant mixtures, 
in which however it is generally prescribed as the simple or com- 
pound tincture of benzoin, or as one of the Tolu preparations. It is 
said to be beneficial in cases in which the mucus is tenacious and is 
coughed up with difficulty. The syrup of Tolu may be regarded 
simply as a flavoring ingredient, for it contains too little of the balsam 
to have any other effect. 

Balsam of Peru and pure cinnamic acid have been administered by hypo- 
dermic and intravenous injection and by the mouth in pulmonary tubercu- 
losis, in the belief that they would induce irritation, inflammation and 
subsequent cicatrization of the tubercular nodules, but there is no reason to 
suppose that they have any such effect, and the treatmen thas never ad- 
vanced beyond the experimental stage. 

When the balsams are administered in large quantities, the addition of an 
acid to the urine is followed by the formation of an abundant precipitate in 
some cases, and this has given rise to the belief that they tend to irritate the 
kidneys. The precipitate appears to be not albumin but the resin in most 
cases, however, for it is dissolved by the addition of alcohol. 

Bibliography. 

Oko'ow. Centralbl. f. Chirurg., 1876, p. 777. 

Kobert u. Schulte. Schmidt's Jahrb., clxxxv., p. 12. 

Salkowski. Zts. f. phys. Chem., i., p. 45. 

C. Virchovi. Ibid., vi., p. 78. 

Stockman. Brit. Med. Journ., 1890, i., p. 1365. 

Kumagavja. Virchow's Arch., cxiii., p. 134. 

Brdutigam u. Nowack. Centralbl. f. klin. Med., 1889, p. 409. 

Richter u. Spiro. Arch. f. exp. Path. u. Pharm., xxxiv., p. 289. 

Wiener. Ibid., xl., p. 313. 

Lewandoivsky. Ztschr. f. klin. Med., xl., p. 202. 

Ulriei. Arch. f. exp. Path. u. Pharm., xlvi., p. 321. 

Nitrobenzol Compounds. 

The nitrobenzol bodies are chiefly of interest because they have often given 
I rise to poisoning of late years from their extensive use in chemical manufac- 
! tures. Nitrobenzol (C 6 H 5 N0 2 ) has also been used to flavor alcoholic liquors, 
and has in this way led to poisoning in some cases. In man nitrobenzol 
causes a grayish-blue, cyanotic color of the skin and visible mucous mem- 
branes, often with nausea, vomiting, great muscular weakness, marked 
dyspnoea, delirium and some convulsive movements of the face and jaws. 



426 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

less frequently of the whole body. Total unconsciousness and coma are 
followed by arrest of the respiration. 

These effects are due in part to changes in the blood, in part to central 
nervous action, in which stimulation and paralysis seem to follow one another. 
The blood is found of a chocolate-brown color, and some of the red cells are 
either deformed or entirely destroyed. Examined with the spectroscope, 
methsemoglobin is very often found in it, while in other cases an absorption 
line is observed between the yellow and the red, which does not seem to corre- 
spond to that of any of the ordinary haemoglobin products, and has there- 
fore been called the nitrobenzol-hsemoglobin line. The blood contains 
a much smaller amount of oxygen than normally, in some cases only 
one per cent, instead of seventeen, and artificial respiration or even shaking 
the blood in air fails to oxidize it further, as the combination of nitrobenzol 
and haemoglobin seems to be incapable of absorbing oxygen. Similar changes 
may be produced in venous blood outside the body by shaking it with nitro- 
benzol. These changes in the blood are the cause of the cyanosis, and the 
imperfect oxidation of the tissues leads to the appearance of a number of 
abnormal products in the urine. (See Phosphorus.) In animals a gastro- 
intestinal catarrh is almost constantly produced unless the intoxication is 
very acute, and this occurs even when the poison is inhaled or injected 
subcutaneously. 

Metadinitrobenzol (C 6 H 4 (N0 2 ) 2 ) has repeatedly given rise to poisoning in 
the manufacture of the modern explosives, such as roburite and securite. In 
action it resembles nitrobenzol, but is more poisonous, and the gastric symp- 
toms are more marked. Amblyopia and a jaundice-like coloration of the 
skin often occur from prolonged exposure to this poison. 

Picric Acid (C 6 H 2 OH(N0 2 ) 3 ) is an irritant to the skin and mucous mem- 
branes, and in large doses causes vomiting and often anuria and strangury. 
A characteristic symptom is the yellow, icteric color of the skin and mucous 
membranes, which is due not to true jaundice, but to the staining of the 
epithelium by the acid. It produces this coloration when taken internally, 
and itching is often complained of, and some eczema or erythema has been 
observed. Violent convulsions occur sometimes, in other cases collapse. 
The urine is yellow or red, and contains some casts but little or no albumin, 
and no bile, the absence of the last serving to diagnose the intoxication 
from jaundice. Picric acid tends to destroy the red cells of the blood in 
animals, but no marked diminution of these has been observed in man. It 
is excreted as picric and picramic acid (C 6 H 2 OH.NH 2 (N0 2 ) 2 ) in the urine. 

Picric acid has been used as a substitute for quinine in malaria, and as an 
antipyretic. An ointment containing it has been applied in some forms of 
eczema, but it gave rise to poisoning in one of the few cases in which it was 
thus employed. 

Bibliography of the Aromatic Nitro-bodies. 

Starkoiv. Virchow's Arch., lii., p. 464. 

Hay. Practitioner, xxx., p. 326. 

Filehne. Arch. f. exp. Path. u. Pharm., ix., p. 329. 

Lewin. Virchow's Arch., lxxvi., p. 443. 

Annino. Schmidt's Jahrb., ccxlviii., p. 127. 

Schroeder u. Strassman. Viertlj. f. ger. Med., 1891, i., Suppl., p. 138. 

Beck. Charite Annalen, xvii., p. 867. 

Munzer u. Palma. Zts. f. Heilk., xv., p. 185. 

Huber. Virchow's Arch., cxxvi., p. 240. 

Naphthylamine. 

Stern has observed a curious and almost unique series of symptoms after 
the administration of several hydrated derivatives of /^-naphthylamine to 
mammals. The most interesting of these were dilation of the pupil and 



BENZOL. 427 

protrusion of the eyeball, and a very marked rise in the temperature, 
amounting in some cases to 4J° C. The dilation of the pupil, which was 
not observed in the later experiments of Fawcett and White, is ascribed by 
Stern partly to local action on the dilator fibres or the terminations of the 
sympathetic nerves in the iris, but mainly to some central stimulation. The 
rise of temperature is produced in part by the output of heat being lessened 
through contraction of the cutaneous vessels, in part by increased oxidation 
in the tissues and augmented heat production. The contraction of the vessels 
is to be attributed chiefly to stimulation of the vaso-motor centres, although 
the drug seems to have some direct effect on the muscular walls of the vessels 
also. Cocaine has a somewhat similar but weaker action, but the naphthyl- 
amine compounds do not produce local anaesthesia. 

Bibliography. 

Stern. Virchow's Arch., cxv., p. 34, and cxxi., p. 376. 
Fawcett and White. Journ. of Physiol., xxi., p. 435. 

Toluylendiamine. 

Toluylendiamine (C 6 H 3 CH 3 (NH 2 ) 2 ) has never been used in therapeutics, 
but it is of importance from the light which it has thrown on some forms of 
jaundice. Stadelmann found that its administration in dogs produced the 
typical symptoms of icterus, while in cats the icterus was less marked, but 
very large quantities of haemoglobin were excreted in the urine. The expla- 
nation of this action is the destruction of the red cells in the blood, which 
leads in the dog to the formation of large amounts of bile pigments in the 
liver. Some of this pigment is reabsorbed from the bile vessels and leads to 
typical jaundice. The absorption is promoted by a curious increase in the 
mucus secretion of the bile ducts, which renders the bile more viscous, and 
by thus delaying its evacuation into the intestine favors its absorption into 
the blood. This increased mucus formation is believed to be due to the 
action of the poison on the secretory cells of the larger bile ducts. The 
formation of bile pigment from haemoglobin liberates large quantities of iron, 
which seems to be stored in the liver, spleen and bone marrow. In the cat 
the haemoglobin is not so largely formed into bile pigment, but escapes in 
the urine. In both animals some methaemoglobin is probably formed. 1 

Bibliography. 

Stadelmann. Arch. f. exp. Path. u. Pharm., xiv., pp. 231 and 422; xxiii., p. 427. 
Engel u. Kiener. Comptes rend, de l'Acad., cv., p. 465. 
Mohrberg. Arb. a. d. pharm. Inst, zu Dorpat, viii., p. 20. 

Benzol. 

Benzol, or benzene, is much less poisonous than its hydroxyl com- 
pounds, but may give rise to symptoms resembling those of phenol when it 
is inhaled in large quantities. It was at one time suggested as a general an- 
aesthetic, but the preliminary excitement is very much greater than that seen 
in the use of chloroform or ether, and partakes much more of a convulsive 
character. Even after unconsciousness and anaesthesia is attained, the char- 
acteristic muscular tremor of the aromatic compounds continues. In sonic 
animals it produces violent and prolouged convulsions, with only partial loss 
of sensation, and even large quantities do not cause the complete relaxation 
of the muscles requisite for surgical operation. It seems to have little or no 
irritant action on the alimentary canal or kidneys in animals, and is excreted 

•A somewhat similar action follows the administration of Cephalanthin, the active 
principle of Cephalanthns occidentalis, Bntton-bush or Swamp dogwood { Mohrberg). 



428 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

in part by the kidneys as phenol double sulphate, in part unchanged by the 
lungs. 

Santesson states that haemorrhages occur very frequently in fatal poison- 
ing in man, and found the same result in experiments on rabbits ; he ascribes 
it to fatty degeneration of the arterial walls, which was well-marked in most 
of his experiments. A number of cases of fatal intoxication are on record, 
some of them arising from the drug being swallowed by suicides, but most of 
them from the accidental inhalation of huge quantities in india-rubber fac- 
tories. Animals exposed to benzol vapor do not seem to absorb enough to be 
seriously poisoned, but when it is injected subcutaneously or applied over a 
large skin area, it proves fatal to them. The benzol of the B. P. contains 
toluene and is used only for pharmaceutical purposes. 

Bibliography. 

Santesson. Arch. f. Hygiene, xxxi., p. 336. Skand. Arch. f. Physiol., x., p. 1. 
Chassevant. Arch, de Pharmacodynam., ii., p. 235. 

Pyoctanine. 

Several of the dyes derived from aniline are used to stain pathogenic germs 
and to differentiate them from each other. This suggested to Penzoldt the 
idea that these bodies, having a distinctly greater affinity for the microorgan- 
isms than for the tissues surrounding them, might be used as antiseptics or 
disinfectants, and Stilling introduced several of them into therapeutic use 
under the name of pyoctanines. Some of these dyes have been found to 
have a certain antiseptic action, but the hopes that were formerly entertained 
as to their specific action have proved delusive, and their use in medicine 
(chromotherapeutics) is now very limited, and promises to fall into oblivion. 

XXVI. FORMALDEHYDE. 

It has recently been shown by numerous investigators that formal- 
dehyde (HCOH), the aldehyde derived from the oxidation of methyl 
alcohol, is a very powerful germicide, while it is only slightly poisonous 
to the higher animals. The aldehyde is a colorless gas and has been 
used either in solution in water (formaline), or as a vapor. As a 
germicide, it is estimated to be equally efficient with corrosive subli- 
mate, and its volatility enables it to penetrate much more rapidly, so 
that it may be used for purposes for which the latter is unsuitable. 

Action. — The vapor is very irritant when inhaled, causing stinging 
and prickling in the nose and throat, salivation and tears, and bronchial 
irritation and catarrh. In the few cases of poisoning in man recorded, 
the symptoms were those of gastric irritation and consequent collapse. 
When swallowed by animals the watery solution produces nausea and 
vomiting, which are followed by narcosis, coma, and in the rabbit by 
convulsions and opisthotonos. The respiration in the dog is very 
greatly accelerated some time before death, while in the rabbit this is 
not so marked or is entirely absent. The blood-pressure is increased 
at first and the heart is slow, presumably from direct or indirect stimu- 
lation of the medullary centres. Part of the formaldehyde absorbed 
has been shown to pass through the tissues unchanged and to be 
excreted in the urine, and it is possible that the whole of it escapes in 
this way. 



FORMALDEHYDE. 429 

The powerful action of formaldehyde on microbes and on mucous 
membranes is believed by Loew to be due to its combining with some 
amide group in the proteids, and as a matter of fact, a number of 
changes have been described in the reaction of proteids exposed to 
formaline. For example, egg albumin and serum to which formal- 
dehyde solution has been added are not precipitated by heat and are 
less easily digested by ferments, while casein is not coagulated by the 
rennet ferment. Some of the ferments ( pepsin, rennet and diastase) 
are not affected by the presence of formaldehyde, while trypsin and 
papain lose their activity wholly or in part. 

Benedicenti states that formaldehyde is a blood poison, causing alter- 
ation in the form of the cells and leading to the formation of haBmatin. 
He is disposed to look upon this effect as the chief factor in the in- 
toxication. 

Peepaeattoxs. 

Formaline, a solution of formaldehyde in water containing 35-40 per cent, 
of the gas which may be obtained from, it by distillation. 

Paraform, a solid polymer of formaldehyde, which is decomposed by heat 
and liberates the formaldehyde in gaseous form. 

Some formaldehyde may be formed by the incomplete combustion of 
methyl alcohol, and several lamps have been devised with this object in 
view, but have not proved entirely satisfactory. 

Uses. — Formaldehyde is too irritant to admit of its use as an anti- 
septic in medicine and surgery, but it has been largely employed to 
disinfect instruments, furniture, clothes and rooms, which cannot be 
sterilized by heat. Diluted formaline (4 per cent.) may be used for 
some of these purposes, or the vapor may be disengaged by distillation 
from formaline, by heating paraform, or less efficiently by the partial 
combustion of methyl alcohol. Large rooms filled with formaline 
vapor and left for some hours are found to be almost completely steril- 
ized, so that cultures of the pathogenic microbes exposed in them cease 
to grow even when removed from the atmosphere. The higher animals 
are much less affected. Xovy recommends that the room to be disin- 
fected be made as nearly air-tight as possible, and the formaldehyde be 
distilled into it through the key-hole of the door. He states that the 
gas disengaged from 150 c.c. (5 oz.) of 40 per cent, formaline is suffi- 
cient for each 1000 cubic feet of space, if the room be closed for 10 
hours. The odor of formaline may then be removed by sprinkling 
ammonia solution with which it forms a solid combination. 

Formaldehyde has frequently been added to food, especially to milk, 
as a preservative. Tunnicliffe and Rosenheim found that added to milk 
in the proportion of one to five thousand, formaldehyde did not seem 
to be deleterious to healthy children, but in the case of a weakly child, 
the proteid waste was increased, and it is certainly not to be regarded 
as a harmless method of preserving food. 

Formaldehyde is not alone in its germicidal action, although it is much 
more powerful than the other less volatile and less active aldehydes such as 
aeetaldehyde. 



430 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

A combination of gelatin and formaldehyde (Glutol) has been employed in 
surgery as an antiseptic powder. The value of urotropine as a genito- 
urinary antiseptic is apparently due to formaldehyde being liberated from it. 
(See Urotropine.) 

Bibliography. 

Loew. Ein Nattirliches System der Giftwirkun'gen, Munchen, 1893, p. 58. 

Aronson. Berl. klin. Woch., 1892, p. 749. 

Dieudonne. Arbeit, a. d. Gesundheitsamt., xi., p. 534. 

Mosso et Paoletti. Arch. Ital. de Biol., xxiv., p. 321. 

Tollens. Bericht. der Deuts. Chem. Gesellsch., 1895, p. 261. 

Pohl. Arch. f. exp. fS^th. u. Pharm., xxxi., p. 295. 

Ermengem et Sugg. Arch, de Pharmacodynara., i., p. 141. 

Aronson. Zts. f. Hygiene, xx v., p. 168, 1897. ,, 

Striiver. Ibid., p. 357. 

Benedicenti. Arch. i. £Anat. u.] Phys., 1897, pp. 210 and 219. 

Novy and Waite. Medical News, lxxii., p. 641 (1898)., 

Bliss and, Novy. a'ovtrn. of Exp. Med., iv., p. 47. 

Tunnicliffe and Rosenheim. Journ. of Hygiene, i., p. 321. 

XXVII. CAMPHOR. 

Some of the volatile oils deposit crystalline substances or stearop- 
tenes after standing for some time, especially when they are exposed 
to cold. As a general rule these bodies are present in only small 
amount, and have not been investigated apart from the volatile oils, 
of which they form constituents ; but a few of them have attracted at- 
tention in therapeutics, not only on account of their local effects, which 
have been described under the volatile oil group (see page 61), but 
also because of their action in the tissues after absorption. The chief 
of these is Camphor, which has been used in Chinese medicine for 
many centuries, and which has also played a considerable role in 
Western therapeutics. It is derived from the Cinnamomum camphora 
of China and Japan, and possesses the formula C 10 H 16 O. Its exact 
chemical structure is not yet understood, but there is no question that 
it is a benzol derivative containing methyl and propyl, in so far re- 
sembling the terpenes, from which, however, it probably differs in the 
presence of a ketone (= CO) link. 

Another body closely resembling ordinary camphor is Borneol or Borneo- 
camphor (C 10 H 18 O), which is derived from the Dryobalanops aromatica, and 
which apparently differs from ordinary camphor in containing the group 
(= CHOH) instead of (= CO). Ngai camphor, which is obtained from Blumea 
balsamifera, is very closely related to borneol. Another stearoptene which 
has been used in medicine apart from the volatile oils, is Menthol (C 10 H 20 O), 
which is obtained from the oil of peppermint, and apparently contains a 
CHOH group like borneol, but is more completely hydrated. Borneol has 
been prepared synthetically from camphor, and menthol from menthane, 
which occurs in oil of peppermint. 

Several derivatives of camphor which have been examined, resemble it 
closely in pharmacological action. Monobromated Camphor (C 10 H ]5 BrO) has 
been used in therapeutics, while Camphorol (C 10 H 16 O 2 ), Camphoric Acid 
(C ft H u (COOH) 2 ), Amidocamphor (C 10 H 15 NH 2 O), Bornylamine (C 8 H 14 (CH 2 )- 
(CHNH 2 )) and some other derivatives have been the subjects of experi- 
mental investigation. 

All of these resemble each other very closely in the effects which 
they produce in the organism, although they vary in toxicity to some 



CAMPHOR. 431 

extent. Many of the volatile oils induce the same symptoms, but as 
these are used almost exclusively for their local action, it has been 
found advisable to treat them separately. The camphor group pre- 
sents analogies to the simpler bodies of the aromatic series, to which it 
is so nearly related chemically, and also to picrotoxin. 

Symptoms. — Camphor acts as in irritant to the skin and mucous 
membranes like the volatile oils, and has a hot, bitter taste, and induces 
in small quantities a feeling of warmth and comfort in the stomach, 
while after large doses nausea and vomiting may be caused by gastric 
irritation. It is rapidly absorbed and in large doses induces headache, 
a feeling of warmth, confusion, and excitement in man, with slowing of 
the pulse and flushing of the skin. This excitement may be shown in 
hilarity and delirium with hallucinations, in restlessness, or in sudden 
violent movements, which pass into epileptiform convulsions. These 
alternate with pauses of quiet and unconsciousness, which become longer 
until the patient sinks into complete stupor. In some cases of 
poisoning no excitement is observed, the patient falling into a condi- 
tion of drowsiness, unconsciousness and stupor immediately. In the 
lower mammals, camphor induces very similar symptoms, wild excite- 
ment and epileptiform convulsions, followed by depression, stupor, 
collapse, and death from failure of the respiration. Not infrequently 
however, the respiration ceases during a convulsion and fails to return 
when it passes off. 

In the frog no excitement is observed except from the local irri- 
tation ; the animal falls into a condition of depression, in which no 
spontaneous movements are made, although the reflexes seem to be 
little affected at first. Later, the reflexes disappear and the animal 
lies completely paralyzed. 

Action : Central Nervous System. — The absence of convulsions in the 
frog has been attributed to camphor paralyzing the terminations of the 
motor nerve ends like curara, but is really due to a descending paralysis 
of the central nervous system. Stimulation of the brain of the frog never 
induces convulsions such as are seen in mammals after cerebral stimu- 
lants, but depression of the brain lessens the spontaneous movements, 
while the reflexes remain. Camphor first depresses the brain in the 
frog, later the spinal cord, and last of all the terminations of the motor 
nerves, and the spontaneous movements cease first, therefore, then the 
reflexes disappear, and finally the muscles fail to contract when the 
peripheral nerves are stimulated. The cord is capable of conducting 
impulses from the brain after the reflexes are paralvzed, so that cam- 
phor would seem to interrupt the connection between the sensory and 
the motor cells earlier than that between the motor columns and the 
cells of the anterior horn. In this respect its action on the spinal 
cord of the frog is diametrically opposed to that of strychnine, and in 
accordance with this, it has been found that camphor acts as an anti- 
dote to strychnine in the frog. The exact action of camphor on the 
spinal cord in mammals is not finally determined, for Stockman found 
that the reflexes were not increased in mammals bv camphor, and 



432 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

he holds that the spinal cord is not primarily stimulated by ordinary 
camphor, and is in fact depressed by borneol. On the other hand, 
Gottlieb and Lapin assert that the reflexes are increased by camphor 
in mammals in which the medulla oblongata has been divided, and 
that in the bird this increased irritability may even give rise to con- 
vulsions. According to them, the spinal cord is finally depressed in 
mammals by very large doses of camphor, but only after stupor and 
coma indicate commencing paralysis of the cerebrum. 

The convulsions in mammals are certainly not due to any action on 
the spinal cord, but to stimulation of the higher areas of the nervous 
axis. It is often stated that the medulla oblongata is the part pri- 
marily involved, but the epileptiform character of the attacks points 
rather to an affection of the cerebral cortex, and Stockman found that 
removal of the cortex prevented the convulsions in mammals. On the 
other hand, Gottlieb observed convulsions after camphor in a pigeon 
in which the cerebrum had been removed. It is not improbable that 
the basal ganglia are also thrown into a state of abnormal activity by 
camphor, as by other poisons which produce similar convulsions. 
The loss of consciousness and the stupor observed in man and the 
higher animals point to a final paralysis of the cerebral cortex. 

The action of camphor on the central nervous system in mammals 
consists, then, in stimulation, followed by paralysis of the cerebral areas 
and probably of other intracranial centres, with less alteration in the 
spinal cord. 

The Terminations of the Motor Nerves are paralyzed in the frog by 
large doses of camphor, but not in mammals. The Muscles themselves 
are weakened and paralyzed when they are directly exposed to its so- 
lutions or vapor. 

The Heart is generally slowed by camphor and its allies in man and 
in most animals, but is sometimes little affected. The frog's heart also 
beats more slowly, but the contractions are stronger and fuller accord- 
ing to most observers, although Lewin found both its absolute force 
and pulse volume lessened. The changes in the heart seem to be due 
to direct action on the muscle, and to be independent of the regu- 
lating nerves. Muscarine fails to induce standstill of the frog's heart 
after camphor, and this has been ascribed to an increase in the irrita- 
bility of the heart similar to that observed under physostigmine. The 
effects of camphor on the mammalian heart are very imperfectly 
known. 

In some mammals the Blood-pressure is considerably increased by 
camphor, in others great variations occur, a very marked rise being 
observed during the convulsive attacks, while in the interval it falls to 
the normal height or even below it. These variations persist after the 
movements are prevented by curara, and would therefore seem to 
indicate that the vaso-motor centre is either acted on directly by cam- 
phor in the same way as the cerebral cortex, or that special impulses 
pass to it from the latter quite independently of those causing the con- 
vulsions. The peripheral vessels have been found to be dilated by 



CAMPHOR. 433 

camphor solutions perfused through them, but it may be questioned 
whether this action comes into play in poisoning ; the dilatation of 
the cutaneous vessels may probably be explained by action on the vaso- 
dilator centres. 

The Respiration is somewhat slower and deeper than normal, but this 
alteration is generally insignificant. During the convulsions it is ar- 
rested, and in the intervals may be accelerated from the muscular ex- 
ertion during the spasms. 

The normal Temperature is not affected by camphor, but in fever it 
acts as an antipyretic, like many other aromatic bodies. 

Camphor is partially oxidized in the tissues, forming camphorol 
(C 10 H l6 O 2 ), this change perhaps being analogous to that observed in the 
aromatic hydrocarbons and phenols. It is Excreted in the nrine in 
combination with glycuronic acid, as a- and ^9-camphoglycuronic acid, 
and also in part in combination with a nitrogenous body, which is prob- 
ably uramidoglycuronic acid. Camphorol acts like camphor, but its 
glycuronic acid combinations are inactive, so that the effects of cam- 
phor pass off quickly in such animals as the dog, in which these com- 
binations are rapidly formed. 

Camphor is possessed of some antiseptic action, although it is much 
weaker than some of the bodies of the carbolic acid group, and also 
than many of the volatile oils. Leucocytes cease their movements at 
once when exposed to camphor solutions or vapor, and Darwin found 
that it acts as a stimulus to the tentacles of Drosera, an insectivorous 
plant, and apparently renders them more sensitive to mechanical irri- 
tation. 1 

Camphor produces redness and a feeling of warmth when rubbed 
into the Skin. Sometimes, however, a distinct sensation of cold may 
be experienced, provided the rubbing is not too energetic. Menthol 
generally induces this feeling of cold, accompanied by more or less 
prickling, and afterwards by heat and burning. The cold is not due 
to cooling of the skin, for the vessels of the part are dilated, and the 
thermometer indicates a higher skin temperature there than in other 
parts of the body. It has been ascribed to menthol being more irritant 
to the terminations of certain nerves which convey the sensation of 
cold than to those of the heat nerves and pain nerves, but this is denied 
by Rollett who states that menthol acts only on the terminations of the 
nerves of common sensation or pain. A feeling of numbness and par- 
tial anaesthesia follows its application after some time, and a ten per 
cent, solution has been found to produce anaesthesia of the cornea, 
which, however, is preceded by pain and smarting. 

The action of borneol, menthol, bromated camphor, camphorol and cam- 
phoric acid is almost identical with that of camphor itself. Borneol is less 
irritant locally, and the convulsions are less severe than after camphor, so 
that animals seldom die during the convulsive stage, and may remain in a 
state of stupor and collapse for one or two days before the respiration finally 

x On the other hand, Vogel's statement that the germination of seeds is hastened by 
the presence of camphor has proved to be incorrect. 
28 



434 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

ceases. After menthol, the convulsions are even less developed than after 
borneol. Both of these are excreted in combination with glycuronic acid. 
Bromated camphor seems to resemble borneol more closely than camphor or 
menthol, while camphoric acid and amido-camphor produce symptoms sim- 
ilar to those of camphor, but are much less powerful. Camphoric acid 
lessens the secretion of perspiration by paralyzing the terminations of the 
secretory nerves in the same way as atropine and agaricin. 

Preparations. 

Camphora (U. S. P., B. P.) (C ]0 H u .O), Laurel camphor, a stearoptene ob- 
tained from Cinnamomum Camphora, forms white translucent, crystalline 
masses, which are almost insoluble in water but dissolve readily in alcohol, 
ether, chloroform, fixedand volatile oils. 0.1-0.6 G. (2-10 grs.), in emulsion 
or pill. 

Aqua Camphorse (U. S. P., B. P.). 

Spiritus Camphors (U. S. P., B. P.), 0.3-2 c.c. (5-30 mins.). 

Linimenttjm Camphors, camphorated oil (U. S. P., B. P.). 

Tinctura Camphors Composita (B. P.), paregoric contains 1 part of 
morphine in 2000, i. e., each fluid drachm is equivalent to \ grain of opium. 
\-\ fl. dr. 

Linimentum Camphorse Ammoniatum (B. P.), compound camphor liniment. 

Camphor is also an ingredient in the camphorated tincture of opium or 
paregoric (U. S. P.) and in soap liniment and chloroform liniment. 

Camphora Monobromata (U. S. P.), monobromated camphor (C ]0 H ]5 BrO), 
consists of colorless crystals which are insoluble in water, soluble in alcohol 
and ether. 0.3-1 G. (5-15 grs.), in emulsion or pills. 

Menthol (U. S. P., B. P.) (C 10 H 20 O), a stearoptene obtained from the 
official oil of peppermint or from Japanese or Chinese oil of peppermint, con- 
sists of colorless crystals slightly soluble in water, freely soluble in alcohol 
or ether. It is used externally in alcoholic solution or moulded into sticks 
and pencils, which are rubbed on the affected part. 

Emplastrum Menthol (B. P.). 

Borneol or Borneo camphor (C 10 H 18 O), a stearoptene obtained from Dryo- 
balanops Camphora, resembles camphor in appearance and solubility, but 
has not been used in therapeutics and is not official. 

Therapeutic Uses. — Camphor is used externally in the form of the 
liniment or spirit as a mild rubefacient in bruises and sprains, and 
also to destroy parasites. Internally the spirit is prescribed as a 
carminative and as an intestinal disinfectant. Its administration for 
the latter purpose has been shown to be followed by a diminution of 
the double sulphates of the urine, so that it seems to retard the putre- 
faction in the bowel to some extent. The spirit is frequently given to 
prevent " chill," and may relieve the congestion of internal organs 
through dilating the skin vessels. 

It was formerly administered in cases of abnormal irritability of 
the central nervous system, such as epilepsy and various other forms 
of convulsions, including those produced by strychnine, but its action 
would seem to contraindicate its use here and camphor is scarcely 
prescribed in these cases now. 

It has been used, apparently with success, as a stimulant to the cen- 
tral nervous system in unconsciousness and collapse arising from dif- 
ferent causes, and in the depression and weakness of acute fevers. In 
many of these cases, a marked improvement in the pulse has been ob- 



CAMPHOR. 435 

served after camphor ; this may be due to the direct action on the 
heart, or may perhaps be explained by its action as a local stomachic 
irritant producing changes in the circulation renexly. Solutions of 
camphor have been injected subcutaneously in these cases, but they 
cause pain and swelling at the point of injection. Camphor is almost 
entirely insoluble in watery fluids and is apparently absorbed slowly 
and with difficulty in some conditions, and this may explain the 
absence of effect in many cases of collapse treated with it. 

Camphor is often prescribed in expectorant mixtures, especially in 
combination with opium, as in paregoric. 

It has been advised in hysteria, and both as an aphrodisiac and as 
an anaphrodisiac. Any effect in these conditions must probably be 
ascribed rather to hypnotic suggestion than to the real action of the 
drug. 

Menthol is used almost exclusively for its effects on the sensory nerve 
terminations, and is applied by rubbing the crystals or sticks on the 
skin in cases of headache and neuralgia. 

Borneol and monobromated camphor are entirely superfluous. The latter 
was at one time used as a sedative in nervous excitement, but does not seem 
to have been at all beneficial and has fallen into disuse. 

Camphoric acid has been found to lessen the night sweats of phthisis 
and is given for this purpose in powder in doses of 1-2 G. It pos- 
sesses the advantage over atropine of acting only on the sweat glands 
in the dose given, and on the other hand has no such action on the 
digestion as is sometimes complained of when agaricin has been pre- 
scribed. Camphoric acid is slowly absorbed and ought to be given an 
hour or more before retiring. It has also been used as an antiseptic, 
but is very much less efficient than salicylic or carbolic acid. 

Bibliography. 

Hoffmann. Inaug. Diss., Dorpat, 1866. 
Huebner. Arch. f. Heilkunde, xi., p. 334. 

Harnack u. Wittkowsky. Arch. f. exp. Path. u. Pharm., v., p. 427. 
Binz. Ibid., v., p. 109; viii., p. 50. 
Pellacani. Ibid., xvii., p. 369. 
Rovighi. Zts. f. phys. Chem., xvi., p. 20. 
Schmiedeberg u. Meyer. Ibid., iii., p. 422. 

Stockman. Journ. of Physiology, ix., p. 65. Edinburgh Med/Journ., 1897, i., p. 45. 
Lewin. Arch. f. exp. Path. u. Pharm., xxvii., p. 226. 
Gottlieb. Ibid., xxx., p. 31. 
Meyer. Ibid., xxix., p. 438. 
Wiedemann. Ibid., vi., p. 216. 

Goklsckeider. Arch. f. Anat. u. Phys., 1886, p. 555. 
Rollett. Pfliiger's Arch., lxxiv., p. 418. 
Bourneville. Practitioner, xiii., p. 112. 
Lawson. Ibid., xiii., p. 324; xiv., p. 262. 
Peters. Inaug. Diss., Dorpat, 1880. 
Lapin. Ibid., 1893. 

Musk, or moschus, is the dried secretion of the preputial follicles of 
Moschus moschiferus, the musk deer of Thibet. It forms a dark, reddish- 
brown, crumbling mass, with a very strong characteristic odor. About \() 
per cent, is soluble in alcohol, about 50 per cent, in water. 



436 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

Musk has long been reputed to have a very powerful action in collapse, 
but is so rarely procurable at the present day, except in a very much adul- 
terated form, that it is comparatively seldom used. Very little is known 
with certainty as to its composition, and the odoriferous matter, which is 
believed to be the active principle, has scarcely been examined. 

In some early investigations, musk was found to cause headache, giddiness 
and confusion, with a feeling of weight and uneasiness in the stomach ; later, 
depression and drowsiness, and eventually sleep. Tremors and even con- 
vulsive movements have also been observed, and the pulse is said to be ac- 
celerated and strengthened. 

Filehue found tremors and contractions of isolated muscle bundles pro- 
duced in the frog from the action of an extract, and concluded that the 
motor terminations were stimulated by it. On the other hand, Hermans, 1 
who studied the subject more recently, could find no effects from the admin- 
istration of musk to men or animals. 

Moschus (U. S. P., B. P.) has been recommended in hysteria and in col- 
lapse, and is prescribed either as a powder, in doses of 0.5-1 G., which may 
be given per rectum when swallowing is impossible, or in the form of the 
tincture of the U. 8. P., in doses of 5 c.c. It is rarely used at the present 
time, and may be considered entirely superfluous. 

Castoreum, the secretion of the preputial follicles of the beaver, was 
formerly used for the same purposes as musk, but was never shown to have 
any effect whatever and has fallen into complete disuse. 

XXVIII. PICR0T0XIN. 

Picrotoxin is the best known member of a group of convulsive poi- 
sons, which resemble each other very closely in action, but of whose 
chemistry little is known beyond the fact that they are devoid of 
nitrogen. It is obtained from the Anamirta paniculata (Anamirta 
cocculus, Menispermum cocculus), and is a neutral indifferent body. 
Picrotoxin (C 30 H 34 O 13 ) may be broken up into picrotoxin in (0 15 H 16 O 6 ), 
which resembles it in its effects on animals, and picrotin (C 15 H 18 7 ), 
which is inactive. 

Other poisons resembling picrotoxin are Cicutoxin, derived from the 
Cicuta virosa, or water hemlock, and probably from other species of Cicuta, 
(Enanthotoxin, the active principle of GEnanthe crocata, water dropwort, or 
dead tongue, and Coriamyrtin, which occurs in several s-pecies of Coriaria, 
of which the best known is the Coriaria myrtifolia or currier's sumach. 
Another species of Coriaria affords the toot poison of New Zealand. Phyto- 
laccotoxin, which has been prepared irom a Japanese species of Phytolacca, 
resembles picrotoxin in its action and may probably be contained in the 
official (U. S. P.) Phytolacca decandra, or pokeberry. Lastly, a number 
of the members of the digitalis series may be decomposed into bodies which, 
devoid of the characteristic cardiac action of digitalis, produce the same 
symptoms as picrotoxin Among these may be mentioned Toxiresin, ob- 
tained from digitoxin, Digitaliresin from digitalin, and Oleandresin from 
oleandrin. These bodies all produce powerful stimulation of the central 
nervous system, more especially of the areas around the medulla oblongata. 
The chemical connection between them and the members of the digitalis 
series has been mentioned already. It may be added that the two groups 
are similar in action in some respects, for although picrotoxin does not affect 
the heart and vessels in the same w r ay as digitalis, the latter possesses the 
characteristic action of picrotoxin on the medulla oblongata, although in a 

inaugural Dissertation, Bonn, 1888. 



PICROTOXIN. 437 

weaker degree ; in fact, some of the remedies described under the digitalis 
series act as strongly on the central nervous system as on the heart. Picro- 
toxin resembles camphor also in its effects. Two alkaloids, Samandarine and 
Samandaridine, recently isolated by Faust from the skin of the newt ap- 
pear to resemble picrotoxin in their effects on animals. 

Symptoms. — The symptoms, which are often somewhat late in ap- 
pearing, are very similar in all classes of vertebrates. In man vom- 
iting is not infrequently observed after members of this series, or the 
first symptoms may be salivation, acceleration of the respiration, and 
some slowness of the pulse and palpitation of the heart. A condition 
of stupor and unconsciousness follows and then a series of powerful 
convulsions, which, commencing in tonic spasms, soon change to 
clonic movements of the limbs and jaws. The respiration is inter- 
rupted during these spasms, but is reinstated during the intervals of 
quiet and collapse which follow them. The convulsions return after 
a short pause, and this alteration of spasm and quiet may continue for 
some time, although the respiration often fails to return after one of 
the spasms, and fatal asphyxia results. 

Similar effects are observed in the lower mammals. After a pre- 
liminary stage in which twitching of the muscles and vomiting often 
occur, and in which the respiration is accelerated, while the pulse is 
slow, a violent emprosthotonic convulsion sets in, but soon changes 
to clonic movements ; these may last for some time, but eventually 
become weaker and give place to a condition of quiet and depression. 
An increase in the reflex excitability is noticeable during this interval, 
the animal is easily startled and occasional twitching of the muscles 
may be observed. Very soon a second convulsion sets in, and this 
may be fatal from asphyxia, but the symptoms often continue for an 
hour or more, violent spasms alternating with periods of depression 
and collapse. In the frog clonic convulsions are also the chief feature 
of the intoxication. Very often the animal becomes distended with 
air during the convulsions, and gives a curious cry in releasing it. 
The heart is always slowed and may cease to beat altogether for 
a time. 

Action. — The clonic convulsions of picrotoxin poisoning are al- 
together different from those of strychnine and other similar bodies, 
which induce prolonged tonic convulsions, and it was early surmised 
that the members of this series act on a different part of the Central 
Nervous System. The convulsions are found to persist in the frog 
after the cerebrum has been destroyed, and even when all of the brain 
above the medulla oblongata has been removed, although they are 
weakened by the destruction of the optic lobes. On the other hand, 
they disappear, or at any rate lose their typical character when the 
medulla oblongata is removed, so that it would seem that picrotoxin and 
its allies act chiefly on the medulla oblongata, while the spinal cord and 
the higher parts of the brain are comparatively little affected. Strych- 
nine, on the other hand, exercises its chief action on the spinal cord, 
while the other parts of the central nervous axis are less affected. It 



438 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

was formerly supposed that picrotoxin stimulated a "convulsion centre" 
in the medulla oblongata, but there is no reason to believe that any such 
definite area exists, and it would rather appear that intense stimulation 
of the medulla in general leads to clonic contractions of the muscles 
throughout the body. The effects of the stimulation of the individual 
centres in the medulla are seen in the acceleration of the respiration, in 
the slow pulse, which is due to inhibitory action, in a very marked rise 
of the blood-pressure, and in the vomiting and salivation. The medulla 
oblongata is not, however, the exclusive seat of action, for in many 
animals the reflexes are found to be increased when the medulla is 
severed from the cord, and this indicates that the spinal cord is also 
more excitable than normally. This action on the spinal cord is best 
seen in the fish and reptile, and is much less marked in the frog and 
mammals. In the former, picrotoxin causes convulsions even after the 
medulla oblongata is removed, but in the higher animals, in which the 
functions are more differentiated, it merely increases the reflexes or 
causes very slight convulsive movements ; and the higher the position 
in the scale of the organism, the more closely is the action of this 
series confined to the medulla oblongata. 

It may be questioned whether the higher divisions of the nervous 
axis are concerned in the picrotoxin intoxication, for though in some 
animals restlessness and increased spontaneous movements are seen, 
they may perhaps be the indirect results of the alterations in the 
respiration and circulation. 

The Heart is rendered slow by picrotoxin, and in the frog may come 
to a standstill during the convulsions. This is due principally to stimu- 
lation of the inhibitory centre in the medulla, since on division of the 
vagi the heart returns to almost its normal rate. Some direct depres- 
sion of the heart is observed after large doses, for the pulse remains 
slowed even after atropine Or division of the vagi. This action on the 
heart is not similar to that characteristic of digitalis, as has been sup- 
posed, but is a paralysis such as is observed after many poisons 
(e. g., chloral). In some cases acceleration of the heart is seen towards 
the end of the intoxication, and this has been supposed to be due to 
stimulation of the accelerating centre. Picrotoxin causes a very marked 
rise in the arterial tension from stimulation of the vaso-constrictor cen- 
tres in the medulla and upper part of the cord. 

The Respiration is accelerated before any convulsions set in, and in 
the intervals between the spasms is also very rapid, owing to the action 
on the centre. Late in the intoxication the breathing may become 
slow and labored, probably from approaching central paralysis. In 
the frog, spasm of the laryngeal muscles prevents the escape of air 
from the lungs, so that the animal becomes enormously inflated. 

The Vomiting often observed in man and the dog under picrotoxin 
is probably of central origin and not due to gastric irritation. 

The peripheral Nerves and Muscles do not seem to be affected by 
these poisons, with the exceptions of toxiresin and digitaliresin, which 
slightly lessen the irritability of the muscles. 






PICROTOXIN. 439 

The fate of picrotoxin in the body and the way in which it is ex- 
creted are unknown. Like other convulsive poisons, it tends to lower 
the temperature when it is given in small quantities so that no con- 
vulsions follow. 

The convulsions of picrotoxin and its allies disappear when chloro- 
form or chloral is administered. On the other hand, the respiration, 
weakened by narcotic poisons such as chloral, is accelerated by picro- 
toxin, the blood-pressure rises, and the sleep is less prolonged. Ani- 
mals are not awakened at once from narcosis by picrotoxin, but coria- 
myrtin has this effect. 

Picrotoxin is not antidotal in morphine poisoning in animals, but 
may possibly be so in man (see page 213). On the contrary, Kossa 
found that very much smaller quantities of morphine were fatal to 
rabbits when half the fatal dose of picrotoxin was given at the same 
time. 

Peepaeations. 

Picrotoxinum (TJ. S. P., B. P.), picrotoxin (C 30 H 34 O 13 ), a neutral principle 
obtained from Anamirta paniculata, slightly soluble in water, much more so 
in alcohol. 0.001-0.003 G. (^ gr.). 

Phytolacca Fructus (U. S. P.), the fruit of Phytolacca decandra or poke- 
berry. 

Extractum Phytolacca Fluidum (TJ. S. P.), 0.3-2 G. 

Phytolacca Radix (U. S. P.), the root of Phytolacca decandra or poke- 
root. 

Therapeutic Uses. — Picrotoxin has been used as an ointment to 
destroy pediculi, and in some forms of skin disease, but is too poison- 
ous to be recommended for this purpose. It has been proposed to 
give it by subcutaneous injection in cases of collapse and in narcotic 
poisoning, but according to Koppen, coriamyrtin is more efficient in 
animals. It has not been employed for this purpose in therapeutics as 
yet. It has some reputation in the profuse night-sweats of phthisis, 
which it diminishes in a certain proportion of cases, probably by in- 
creasing the respiration and thus preventing the stimulation of the 
nervous mechanism of perspiration through the partial asphyxia. 
Phytolacca has been advised as an emetic, but is slow in action and 
dangerous. It is seldom prescribed, and appears to be superfluous, 
at any rate until its action has been ascertained with more certainty. 

BlBLIOGEAPHY. 

Roeber. Arch. f. Anat. u. Phys., 1869, p. 38. 

Luchsinger. Pfliiger's Arch., xvi., p. 530. 

Kossa. Ungar. Arch. f. Med., i., p. 24. 

Browne. Brit. Med. Journal, 1875, i., p. 409. 

Koppen. Arch. f. exp. Path. u. Pharm., xxix., p. 327. 

Gottlieb. Ibid., xxx., p. 21. 

Harnack. Ztsch. f. klin. Med., xxv., p. 16. 

Boehm. Arch. f. exp. Path. u. Pharm., iii., p. 224; v., p. 279. (Cieutoxin. ) 

Pohl. Ibid., xxxiv., p. 259. (Cieutoxin and OEnanthotoxin. ) 

Perrier. Ibid., iv., p. 191. (Toxiresin, Digitaliresin, etc.) 

Faust. Ibid., xli., p. 229; xliii., p. 84. (Samandarin.) 



440 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

XXIX. THE DIGITALIS SERIES. 

The digitalis series embraces a considerable number of substances 
which are characterized by their action on the heart. They are widely 
distributed in the vegetable kingdom in very different botanical fam- 
ilies, and have long been in use for various purposes in civilized and 
uncivilized countries. Some of them were employed as remedies by 
the laity long before their virtues were recognized by the medical pro- 
fession, while others have been used as arrow poisons by the natives of 
different parts of Africa and of the Eastern Archipelago. 

The most important plants which contain bodies belonging to this 
group are Digitalis purpurea (purple foxglove), Strophanthus hispidus, 
Kombe, and Scilla maritima (squills). Others which are less fre- 
quently used are Helleborus niger l (Christmas rose), Convallaria rna- 
jalis (lily of the valley), Apoeynum cannablnum (Canadian hemp), and 
Adonis vernalis (pheasant's eye). Similar effects are obtained from 
bodies contained in other species of these genera and in a large and 
ever-growing list of other plants, such as Antlarls (Upas tree), Neriwm 
(oleander), Acokanthera (ouabaio), Erythrophlceum (sassy bark or Casca 
bark), Thcvetla, Urechites and Coronllla. 2 Numbers of other plants 
are said to resemble digitalis in their effects, but until this has been 
shown by more careful investigation, it is undesirable to add them to 
the above list, which is already extensive enough. Many of the arrow 
poisons certainly contain digitalin bodies, but even their botanical 
origin is unknown in many instances. These bodies are not, however, 
confined to the vegetable kingdom, for Faust has recently isolated two 
substances 3 from the skin of the toad, which induce the same changes 
in the heart, and the Epinephrine of the suprarenal capsule (see supra- 
renal gland) has been recently shown to have very similar effects. 
Salts of barium also induce many of the changes characteristic of this 
series. 

The active principles of the plants of this group present many points 
of resemblance, and some of them which are now believed to be distinct 
may prove to be identical. Their isolation is attended with consider- 
able difficulty, as many are amorphous, and but few of them form 
combinations with the ordinary chemical reagents. Most of them are 
glucosides, others are indifferent bodies, and one or two are alkaloids. 
There are often found in a plant several distinct bodies belonging to 
this series, and these may again be accompanied by others which in- 
duce the same symptoms as picrotoxin or saponin. 

Digitalis has been more carefully examined from the chemical point 
of view than the other plants, but even its active principles are still 
only partially known, and the subject is yet in an unsatisfactory state ; 
for the amount and character of the active constituents seem to vary 

1 This must not be confused with green and Avhite hellebore (see page 338). 

2 Cactus grandiflorus ( Cereus ), which has been recommended as a substitute for digi- 
talis, has no similar action and does not belong to this series. 

3 These are named Bufonin and Bufotalin and appear to be nearly related to choles- 
terin . 



THE DIGITALIS SERIES. 441 

not only in different seasons and in plants grown in different soils, but 
also in different parts of the same plant. The chief active principles 
were isolated by Schraiedeberg in 1874 and his statements have more 
recently been confirmed and extended by Kiliani. There appear to 
be at least four glucosides in digitalis which possess the characteristic 
cardiac action — Digitoxin, Digitophyllin, Dlgitalin and Digitalein — 
and these are accompanied by one or more glucosides (Digitonin) which 
have the irritant action of saponin and like it suspend insoluble bodies 
in water. The pharmacopoeial preparations are made from the leaves, 
in which digitoxin and digitophyllin are the most important constitu- 
ents, though a small quantity of another glucoside resembling digitalin 
is also present. These glucosides are practically insoluble in water 
when pure, but are taken up from the leaves by water owing to the 
presence of the digitonins, so that the infusion of digitalis leaves is a 
very powerful preparation. The active glucosides are more soluble in 
alcohol, while digitonin is insoluble, so that the tincture contains prac- 
tically the same constituents as the infusion except digitonin. 

The seeds of digitalis are not pharmacopoeial, but are extensively 
used for the preparation of the so-called digitalines of commerce. They 
contain digitalin and digitalein in large amounts with a small percen- 
tage of digitoxin and a larger proportion of digitonins than the leaves. 
Digitalin is less insoluble in water than digitoxin and digitalein is 
freely soluble. The preparations from the seeds thus differ entirely 
from the Galenical preparations which are formed exclusively from the 
leaves, and most clinicians find them less satisfactory in practice. 
Digitoxin is much the most powerful constituent, and the small amount 
in which it is present in the digitalines prepared from the seeds prob- 
ably accounts for their unsatisfactory effects in therapeutics. 

Strophanthus Kombe contains a crystalline glucoside, strophanthine 
while other varieties of strophanthus such as S. hispidus contain another 
glucoside, pseudo-strophanthin, which is probably nearly related to stro- 
phanthin but is about twice as poisonous. Another glucoside — Oua- 
bain or Aeokantherin — is found in Strophanthus glaber and in Aco- 
kanthera and is also closely related to strophanthin. Some of the 
strophanthus genus contain non-glucosidal active bodies. The stro- 
phanthin of commerce is generally derived from a mixture of different 
species and varies much in composition and toxicity. 

Scilla maritima or squills is said to contain Scillain, a glucoside, very 
soluble in alcohol, scarcely so in water, but this requires further in- 
vestigation. Several other active constituents have been described in 
squills, but none of them have been actually isolated, and they may be 
merely impure forms of scillain. Saponin bodies are also present. 

Helleborus niger contains Helleborein, a glucoside, which is very 
soluble in water, and resembles digitalin in action, and Hcllcborin, 
which is insoluble in water and has an entirely different effect. 

Convallamarin (obtained from Oonvallaria), Adonidin (Adonis), Oleandrin, 
Neriin and Neriodorin (Nerium), Euonymin (Euonymus), Antiarin (Antiaris), 
Thevetin and Cerberin (Thevetia), Cheiranthin (Cheiranthus), CoroniUin (Coro- 



442 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

nilla), Tanghinin (Tanghinia venenifera), and Apocynein (Apocynum), are 
glucosides, while Apocynin (Apocynum) is indifferent and Erythrophlceine 
(Erythrophlceum guinense) is a glucosidal alkaloid. 

With the exception of the last, then, the members of this series which 
have been examined hitherto are either glucosides or indifferent-eubbtancee, 
containing carbon, hydrogen and oxygen, but no nitrogen. They are all 
liable to decompose when kept long in watery solutions, and especially when 
heated with acids, and then frequently form substances which no longer pos- 
sess the digitalin action, but are rather to be classed with picrotoxin. (See 
page 436.) It will be shown later that even digitalin and its congeners have 
this picrotoxin action to a greater or lesser degree, and it seems probable, 
therefore, that all of them are derivatives of some common nucleus, which 
belongs to the picrotoxin series, but which in combination assumes a new 
character through its action on the heart and vessels. 

Erythrophlceine and a more recently isolated alkaloid, Muawine, which 
resembles it in most respects, split off a molecule of sugar when they are 
boiled with acids. This glucosidal reaction perhaps indicates that they are 
more closely related to the other members of the series than would appear 
at first sight. 

Action. — The digitalis series possesses a local and a general action. 
The Local Effects consist in primary irritation, followed frequently 
by paralysis of the sensory nerve endings. Thus in the eye a small 
quantity of a solution, or a minute particle of the dry poison causes 
the most intense pain, redness and congestion of the conjunctiva, and all 
the symptoms of an acute inflammation. On the tongue the bitter taste 
is followed by burning pain frequently, and if the powder be drawn 
into the nostrils and larynx, marked swelling of the mucous membrane, 
sneezing, coughing and hoarseness are produced in many persons. They 
have little action on the skin, although here too smarting is occasion- 
ally produced ; but when injected subcutaneously many of them cause 
marked inflammation, which not infrequently ends in the formation of 
abscesses, even although the injection has been absolutely aseptic. The 
same irritant action is produced in the stomach by several of them, 
and, in fact, by all of them when taken in very large quantities or for 
long periods. This irritant action is not equally marked throughout 
the series, however, for digitoxin is much the most powerful in this 
respect, while digitalin may be injected subcutaneously without danger 
and without pain. Their local irritant action explains the use of squills 
as an emetic, and of euonymus as a purgative. The local anaesthetic 
property is likewise not equally developed in all the members of the 
series ; several of them (strophanthin, ouabain, erythrophlceine) have 
been suggested as local anaesthetics for the eye, but their primary irri- 
tant effect precludes their use for this purpose. 

After absorption, the chief symptoms are due to their action on the 
central nervous system, the heart, and the vessels, more especially on 
the two last. The action on the Central Nervous System is frequently 
ignored or attributed to the changes in the heart as a secondary effect, 
but there is undoubtedly a stimulation of some of the nerve centres, 
quite independent of the action on the heart and vessels. This stimu- 
lation, like that of picrotoxin, seems almost entirely limited to the 
medulla oblongata in many cases. In the frog the excitability of the 



THE DIGITALIS SERIES. 443 

reflexes is often lowered by members of this series, probably because 
of the intense stimulation of the medulla oblongata ; but sometimes a 
distinctly increased irritability is observed. These alterations are much 
greater than those caused by the interruption of the circulation, and 
are therefore independent of the action on the heart, to which they have 
been erroneously ascribed. More marked symptoms are produced in 
mammals, however, by this central nervous stimulation, for in these 
vomiting is elicited very soon after the injection of large quantities, 
long before the heart is very seriously affected, and this is undoubtedly 
due to action on the medulla oblongata. To the same cause is to be 
attributed the rapid, deep respiratory movements and convulsions, 
which are often observed in the later stages of poisoning, and which 
are evidently not due to cerebral anaemia, as has been supposed, for the 
brain at this stage receives quite as much or more blood than it nor- 
mally does. Even small quantities, such as are used therapeutically, 
cause stimulation of certain parts of the central nervous system, for the 
activity of the inhibitory cardiac centre in the medulla is the cause of 
the slowness of the heart which is seen in therapeutics and in experi- 
ments on mammals. 

The central nervous system, then, undergoes distinct stimulation un- 
der digitalis. This stimulation by small quantities seems limited to 
the inhibitory cardiac and the vaso-constrictor centres in the medulla 
oblongata, but when larger doses of digitalis and its allies are injected, 
other parts of the medullary centres become stimulated, and vomiting, 
increased respiration and eventually general convulsions may be pro- 
duced. 

The extent to which the members of this series act as stimulants to 
the nervous centres varies, erythrophloeine seeming to approach more 
nearly to picrotoxin than the others, while helleborein is among the 
least active, but as yet little comparative work has been done in this 
direction. 

The action on the Heart is the most important of all, and is what 
distinguishes digitalis and its allies from all other substances. This 
action has been studied most carefully in the frog, and is found to be 
due to an alteration in the cardiac muscular tissue. On exposing the 
frog's heart, and watching its movements after the injection of digitalis, 
the muscular action can generally be made out very distinctly (Fig. 27). 
The heart becomes slower in rhythm, and contracts to smaller dimensions 
in systole, while it does not dilate so fully in diastole. The ventricle 
is therefore whiter during systole than normally, while during diastole 
it does not seem so purple, owing to its containing less blood at each 
period. The slowing can be seen to be due to the heart remaining 
contracted longer than usual, while the dilatation is very short and 
imperfect. Later the apex of the ventricle ceases to dilate during 
diastole, and remains quite still while the base still dilates after each 
auricular systole. Or the whole ventricle dilates only once for every 
two contractions of the auricle, or the two halves of the ventricle may 
contract alternately so that the blood is thrown from one side to the 



444 



ORGANIC DRUGS ACTING AFTER ABSORPTION. 



other. Meanwhile the duration of systole becomes still more prolonged, 
and the extent of diastolic dilation diminishes until the ventricle finally 
ceases to contract, remaining in a position of extreme systole with its 
cavity obliterated. The auricles come to a standstill also, but they 
are unable to empty themselves into the contracted ventricle and there- 
fore remain distended with blood. The typical action of digitalis on the 
muscle of the frog's heart, then, consists in a tendency to increased 
and prolonged contraction, and diminished and shortened diastole. 

In some cases certain other features appear in the frog's heart, for the 
slow rhythm may be accompanied by a less perfect systole, and instead 
of the heart ceasing in systole, it may come to a temporary standstill in 
a state of extreme diastolic dilatation. This is due to stimulation of 



Fig. 37. 



D 




/ 



V 



V 




Tracing of the movement of the frog's ventricle under digitalis. The lever forms an upward stroke 
during systole. A, normal ; B, the systole is somewhat more complete and is very prolonged, and 
the rhythm is correspondingly slow. C, the ventricle remains in systole with occasional feeble dias- 
tolic movements. D, the diastoles of the heart have almost entirely ceased. A', diagram of the heart 
of the frog in its normal dimensions, a, auricle ; v, ventricle with the aortic bulb rising from it. 
The dotted line in the ventricle represents the outline in systole, the continuous line the outline in 
diastole. D' , outline of the heart in the standstill after digitalis. The ventricle v is very much con- 
tracted, the auricle a distended with blood. 

the vagus centre in the medulla, and must be carefully distinguished 
from the action on the cardiac muscle. Not infrequently the two forms 
occur in combination, or the symptoms of inhibitory action precede 
those of the true cardiac change. 

The amount of blood expelled by the heart varies according to the 
degree to which each of these factors comes into play. If the dilata- 
tion in diastole is unchanged or increased, while the contraction is 
greater than normal, the amount of blood expelled by each beat is of 
course increased, but as the dilatation becomes less, the amount ex- 
pelled diminishes until it reaches zero. Even though the amount of 
blood expelled by each beat is increased, one finds not infrequently 
that the total output per minute is diminished because the rhythm is 
so much slower than usual. 



THE DIGITALIS SERIES. 



445 



The irritability of the heart muscle is also found to be considerably 
increased by digitalis. Thus if the ventricle of the unpoisoned frog's 
heart be excised, and salt, solution be led through it, it ceases to beat 
after some time. If, however, a small quantity of digitalis be added 
to the salt solution, rhythmical contractions are often induced and the 
heart eventually passes into systolic standstill. This increased irri- 
tability may explain a temporary acceleration of the cardiac rhythm, 
which is occasionally seen in frogs and in other cold-blooded animals. 

The nature of the action on the cardiac muscle has been a good deal 
discussed. Schmiedeberg brought forward the theory that it was 
mainly an increase in the elasticity of the heart muscle, but this has 
been disputed by Roy, who showed that it was not sufficient to explain 
the phenomena. With the present knowledge of the molecular changes 
which occur in the heart, it is impossible to proceed beyond the state- 
ment that the muscle tone is increased, and that thereby the relaxation 

Fig. 38. 





D 



N 



Tracings of the ventricular contractions under digitalis in experiments on two dogs. N, N', normal 
contractions. D, D' , contractions under digitalis. The levers move upwards during systole. In D 
the rhythm is slower and the movements extend further upwards and downwards than in N, >'. e., the 
contractions are more complete and the dilatation during diastole is greater. In D' the rhythm is 
slower, and the tracing extends further upwards than in N', but reaches almost the same point below, 
i. e., the contraction is stronger, but the dilatation is scarcely changed. Contrast the effects of inhibi- 
tion alone in Figs. 27 and 29 (pp. 289 and 319). 



of the muscle is rendered less perfect and the contraction more complete 
and prolonged. The inhibitory action of the vagus, on the contrary, 
tends to render the tone less complete, and to produce less complete 
contraction and more complete diastole. The direct effects of digitalin 
on the cardiac muscle of the frog are therefore diametrically opposed to 
those of inhibitory activity. 

The hearts of some invertebrates, such as of the snail, are said to 
undergo changes similar to those described in the frog's heart, while the 
crustaceans seem to be entirely unaffected by digitalis. 

The action on the frog's heart is of great interest, because the changes 
produced by this series on the mammalian heart partake largely of the 
same character. The inhibitory and the muscular actions are again 
opposed to each other, but here the inhibitory is almost invariably 
present to a greater or less degree. The action of digitalis and its allies 
on the mammalian heart may be divided into three stages, of which the 
first and the third are always developed when sufficient quantities are 



446 



ORUAMC UIWGS ACTING AFTER ABSORPTION. 



Fig. 



administered. The second stage may be absent in certain circum- 
stances, but is also generally present in poisoning. 

In the first or therapeutic stage of the action of this series, the rhythm 
of the heart is changed, and the extent of contraction and relaxation 
of the ventricle and auricle undergo certain modifications (Fig. 38). 
The rhythm of the heart is distinctly slower than before giving the 
drug, for the inhibitory apparatus is set in activity, and the slowing is 
accordingly due to a prolongation of the pause in diastole. The ventri- 
cles contract to a smaller size, that is, they empty themselves much more 
completely than they normally do. It is now universally recognized 
that the normal ventricle does not empty itself completely ; that even 

at the end of its systole there 
still remains some blood in 
its interior. After the action 
of this group has begun, how- 
ever, the blood remaining at 
the end of systole is much 
less than before. This in- 
creased contraction is, like 
that in the frog's heart, due 
to action on the cardiac mus- 
cle, and leads to an augmented 
pressure in the ventricle dur- 
ing systole. The papillary 
muscles undergo the same 
changes as the rest of the 
ventricular wall, contracting 
more strongly and more com- 
pletely than before the ad- 
ministration of the drug. 

The relaxation of the ven- 
tricle is found to vary in dif- 
ferent conditions. If the 
heart is weak and dilated, 
digitalis and its allies tend to 
lessen this dilatation, that is, 
the relaxation of the ventricle 
during diastole is less than 
before the administration of the drug. (See Fig. 39.) If, however, 
the heart is normal, or does not dilate much during diastole, digitalis 
increases the relaxation. (Fig. 38, D.) The variation in the degree 
of dilatation of the ventricle depends upon the opposing factors — the 
inhibition and the muscular action. If the inhibition be the stronger, 
the ventricle relaxes more completely than before, for vagus stimula- 
tion always tends to increase the relaxation of the heart. If, on 
the other hand, the muscular action predominates, the relaxation is 
lessened, for here, as in the frog's heart, this series tends to lessen 
the extent of relaxation. In the normal heart the application of one 




B A 

Tracings of the movements of the ventricle (lower) 
and auricle ( upper) under digitalis. During systole the 
levers make an upstroke. In this experiment the in- 
hibitory terminations had been paralyzed, so that only 
the muscular action is developed. J, "normal ; B, after 
digitalis. The rhythm of the heart is slightly acceler- 
ated in B, and the levers extend further upwards, indi- 
cating a more perfect systole in both auricle and ven- 
tricle. The ventricular lever does not reach so far 
downwards in B,i. e., the ventricular diastole is less 
complete. 



THE DIGALITIS SERIES. 



447 







of this series causes, as a general rule, an increase in the extent of 
relaxation. 

It must be added that the inhibition is due in part to stimulation of 
the intra-cardiac inhibitory apparatus, but mainly to the stimulation 
of the vagus centre in the medulla. This is shown by cutting the vagi 
before the injection, for the slowing is then much less than when the 
vagi are intact, or may be entirely absent. 

If, then, the ventricles contain more blood at the beginning of sys- 
tole, i. e., are more relaxed than usual, and if the quantity remaining 
at the end of systole is less than normal, the heart must expel much 
more blood at each ventricular contraction than it does normally. (See 
Fig. 40.) Even though the 

amount of blood at the be- Fig. 40. 

ginning of systole is un- 
changed or slightly dimin- 
ished (lessened dilatation), 
as occasionally happens, the 
amount expelled is increased 
because the ventricles con- 
tract more completely. If 
the number of beats per 
minute remained the same, 
therefore, the amount of 
blood expelled (or the out- 
put) would be much increas- 
ed ; but the rhythm is slower 
than normal, and although 
each beat propels a larger 
amount of blood into the 

aorta and pulmonary artery ^ (normal) and in B it i'can ^also rise higher. The output 
-t . . ■ . of each stroke is represented by the shaded part of the cvl- 

than normally, it is not im- 
possible that the output may 
be less than before the drug 
was administered. In the 
therapeutic use of these 
drugs the slowing is not 
great enough to Counterbalance the increased output per beat, and a larger 
amount of blood is therefore driven into the aorta and pulmonary artery. 

The more complete contraction of the ventricle also causes a higher 
pressure in its interior than before, and the blood is therefore expelled 
into the vessels under greater pressure than normally. 

The changes in the ventricle, then, are due to inhibitory activity and 
to direct cardiac action, the first tending to lessen the number of beats, 
to increase the relaxation of the fibres and to weaken the systole, and 
thus to diminish the output and efficiency of the heart ; the second 
tending to strengthen the systole and thus to augment the output, while 
also limiting the dilatation, which may increase or lessen the efficiency 
of the heart according to circumstances. 




Diagram to illustrate the effect of digitalis on the output 
of the ventricle. A, B, C, three cylinders with pistons 
moving up and down in them and driving out fluid. In B 
and C (digitalis action), the piston descends lower than in 



inder and is greatest in B, in which more fluid is present 
at the beginning of the stroke (diastole) and less at the end 
of the stroke (systole) than in A. It is also greater in C, 
in which the same amount of fluid is present at the begin- 
ning of the stroke (diastole) as in A, but less is present at 
the end (systole). If the pistons make the same number of 
strokes per minute in A, B and C, the amount of fluid 
pumped will be greatest in B and least in A, which repre- 
sents the normal ventricle. 



448 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

In the auricles the same two agencies are found in opposition, the 
inhibitory stimulation and the muscular action. Stimulation of the 
inhibitory nerves causes in the auricle no dilatation, or but a very 
slight one, while it lessens the contraction considerably, and in fact 
may prevent it entirely. The muscular action of this series is the same 
here as in the ventricle, causing a tendency towards more complete 
systole and less complete relaxation. After small quantities, such as 
are used in medicine, the rhythm of the auricle is slow, like that of the 
ventricle, owing to the inhibition ; the relaxation is little changed, but 
owing to the muscular action, the contraction is more complete. In 
but slightly larger quantities, however, the inhibitory action causes a 
less complete contraction, so that the work done by the auricle is actu- 
ally less than before the injection. 

The rhythm of the different parts of the heart is exactly the same 
during this stage, and the changes seen in the right auricle and ventri- 
cle correspond to those in the left. 

If larger quantities be injected, either the inhibitory or the muscular 
action may become markedly increased, and the appearance of the 
heart varies according to which of these predominates. It must be 
distinctly understood that the following symptoms betoken a grave 
condition of poisoning and are not met with in the therapeutic use of 
the series. 

In the second stage, the symptoms are due to excessive inhibitory 
activity, while the direct cardiac action is less developed. The 
rhythm of the ventricle, and consequently of the pulse, is very slow 
and irregular, as is always the case when the inhibitory apparatus is 
strongly stimulated (see Fig. 27, p. 289). During diastole the ven- 
tricle dilates more completely than usual, while its systole varies in 
strength. If the muscular action is well developed, it continues to 
empty itself more completely than usual, but very often the inhibition 
is so powerful that the muscular action is entirely concealed and the 
systole is weaker and more blood remains at the end of the contrac- 
tion than before the drug was administered. As a general rule, how- 
ever, each beat expels more blood than normally, because the heart is 
engorged before the systole begins ; but the rhythm is so slow that 
the output per minute and the efficiency of the heart as a pump is less 
than usual. This is the feature which differentiates the first from the 
second stage, in which the same factors are present ; in the first stage 
the efficiency of the heart, i. e., the amount of blood expelled per 
minute, is greater, in the second stage less than before the administra- 
tion of the drug. 

Not infrequently the auricle and ventricle beat in different rhythms, 
the ventricle developing a spontaneous rhythm which may be either 
faster or slower than that of the auricle. This is apparently due to 
the inhibitory action, which blocks the passage of impulses from the 
auricle to the ventricle, although the effect of the drug in increasing 
the irritability of the cardiac muscle may contribute to it by facilitat- 
ing the development of the spontaneous ventricular rhythm. 



THE DIGITALIS SERIES. 



449 



The auricular contractions are much weaker than in the first stage, 
and even than in the normal heart, and may cease altogether for 
some time, while the chambers do not tend to dilate further as a 
general rule. 

Although the rhythms of the auricle and ventricle may differ at 
this stage, the two ventricles always beat in unison, and the changes 
in the strength of their contraction and in the extent of the relaxation 
are similar. 

This stage of excessive inhibition is not observed in every case of 
poisoning in animals, nor probably in man, although in the recorded 
instances of poisoning with the members of this series, it seems to have 
been present, as the pulse is said to have been very slow and irregular. 



Fig. 41. 



lllp^^ 




Tracing of the auricular (upper) and ventricular movements (lower) under digitalis, as the first 
stage passes into the second. During systole the levers move upwards, during diastole downwaids. 
The rhythm of the two chambers is at first the same, but sood changes, the auricle maintaining its 
rapid beat while the ventricle becomes slow and irregular. At the end of the tracing the ventricle 
again becomes rapid, while the auricle becomes slow. The strength of the contractions and the extent 
of relaxation of the ventricle muscle remain little altered, while the auricle rapidly weakens in 
strength, but improves again at the end of the tracing. 

Therapeutic doses of these drugs never induce irregularity in them- 
selves, though the pulse is often irregular from disease in the cases in 
which they are prescribed. When in their therapeutic use irregular- 
ity arises from their effects, the physician is inducing the second stage 
of poisoning, in which the efficiency of the heart is less than it would 
be without the drug, and the dose ought to be reduced at once. If 
the inhibitory mechanism is weak or is paralyzed by the preliminary 
injection of such drugs as atropine, the second stage is entirely absent. 

When very large quantities of any of this series are injected, the 
third stage sets in. It is preceded by the first for a short time, gener- 
ally by both first and second. In this stage the ventricular rhythm 
becomes very much accelerated, often beyond the normal, and even 
beyond that seen after paralysis of the inhibitory nerves. This ac- 
celeration has often been supposed to be produced by paralysis of the 
vagus, but this is not Os correct explanation, for stimulation of this 
nerve sometimes still slo\v& the heart and always causes dilatation. 
The acceleration is really due ro the drug increasing the irritability of 
the heart muscle to such an extent that the inhibitory apparatus is no 
longer able to hold it in check. 
29 



450 



ORGANIC DRUGS ACTING AFTER ABSORPTION. 



The auricles also undergo the same changes. They begin to accel- 
erate their rhythm, and if the second stage has not developed, they 
continue in the same rhythm as the ventricle. If, however, the ven- 
tricular rhythm has been independent of the auricular in the second 
stage, the auricles are often later in being accelerated than the ven- 
tricles, because the inhibitory nerves act more strongly on them. The 
difference in rhythm of the two divisions leads to a very characteristic 
periodic variation in the strength of the contractions of both auricle 
and ventricle. This auriculo-ventricular arhythmia may continue for 
some time, but further irregularities soon present themselves. At in- 
tervals, asystole of either 
Fig. 42. ventricle or auricle ap- 

■' i i i i i i i i i i i i i pears, that is, two con- 

tractions follow so rapid- 
ly on each other, that 
the chamber has no time 
to dilate fully between 
them and no blood is ex- 
pelled by the second one. 
These asystolic contrac- 
tions become more nu- 
merous, and soon form 
groups of two or three, 
separated by other groups 
of ordinary contractions. 
The rhythm becomes 
more and more rapid, 
and other forms of irreg- 
ularity appear, which it 
is impossible to describe there. Eventually the auricle generally passes 
into delirium cordis while the rhythm of the ventricle continues to 
increase, and the force of its contractions and the output of each beat 
decrease. The ventricle finally passes into delirium cordis also, and 
the circulation is arrested, after which the heart dilates to an extreme 
degree. 

All the features of the third stage are due to the poisons increasing 
the irritability of the heart muscle. This leads to acceleration of the 
beat, and, eventually, through the muscle of one pair of chambers 
being acted on more than that of the other, to arhythmia. The asys- 
tolic contractions are evidently of the same origin, and the final delir- 
ium is also to be ascribed to this action. Almost all the characteristic 
features of this stage may be imitated in the normal, unpoisoned heart 
by stimulating the different chambers by electric shocks ; the impulses 
which in the poisoned heart arise from it-p ,wn excessive irritability 
are here given by the artificial stimuli, birt the effect is the same. 

The output of the heart continues much augmented during the first 
part of the third stage, but, as the irregularity of the ventricles in- 
creases, and the asystolic contractions become more numerous, it be- 




Tracing of the ventricular movements in the last stage 
digitalis poisoning. The lever moves upwards in systole. The 
characteristic feature is the extreriie irregularity, no two con- 
tractions resembling each other in form or strength. 



THE DIGITALIS SERIES. 451 

comes less and eventually falls to zero when the heart passes into de- 
lirium. Throughout the whole course of the intoxication the ventricles 
beat in unison, no interventricular arhythmia, such as has been de- 
scribed by some authors, being noticeable at any stage. The two 
auricles often differ somewhat in their rhythm in the third stage, and 
the rhythm of the ventricles may, as has been stated, be entirely dif- 
ferent from that of the auricles in either the second or third stage. 

The effects of digitalis on the mammalian heart therefore resemble 
in general those observed in the frog's. The contraction is not pro- 
longed, however, as it is in the latter, and the inhibitory mechanism 
plays a more important role. The irregular stage evidently corre- 
sponds in each, and the final delirium cordis in the mammal represents 
the continued contraction in the frog, the mammalian heart not being 
capable of a continued systole. The heart in mammals is generally 
found in a condition of diastole in cases of fatal digitalis poisoning, 
and this has been supposed to indicate a fundamental difference in the 
action of digitalis on the amphibian and mammalian heart. The dila- 
tation is not, however, a direct result of the digitalis but is probably 
induced by the poisons formed in the heart by its own activity. 

Another explanation of the cardiac action of digitalis refers much of what 
has been called muscular action hitherto, to stimulation of the terminations 
of the accelerans nerve, but no evidence has been brought forward as yet 
that these nerves are involved in the effects, and it is impossible to explain 
many of the features of the third stage by accelerans action. 

The Peripheral Vessels are affected in several ways by the members 
of this series. The increased output of the heart in the therapeutic 
stage augments the pressure in their interior, and it seems not unlikely 
that the vaso-motor centre is stimulated and that this causes a con- 
traction of the arterial walls. But in addition to these effects, the 
muscular wall of the arterioles is constricted by a direct action of the 
glucosides and the resistance to the flow of blood from the arteries to 
the veins is increased, which further raises the tension in the aorta 
and larger arteries. It seems likely that all the members of the group 
do not act equally at all three points, but very little is known defi- 
nitely on the subject except that digitoxin acts more powerfully on the 
vessels than some of the others, and that erythrophloeine acts more on 
the medulla and less on the heart than any other glucoside hitherto 
examined. 

All the digitalis bodies then increase the arterial blood-pressure 
partly through changes in the heart, and partly through contraction 01 
the vascular walls. There is on the one side an unusually large 
amount of blood expelled by the heart, on the other, unusual resist- 
ance to its passage out of the arteries. And this appears to be the 
final result when digitoxin is injected. But when strophanthin, digi- 
talin or convallamarin is used, a further complication arises, for these 
have a somewhat less marked vascular action, and though the vessels 
of the abdominal organs are contracted in the same way as by digi- 



452 



ORGANIC DRUGS ACTING AFTER ABSORPTION. 



toxin, those of the extremities dilate. This dilation is partly owing to 
the increased pressure in the interior overcoming the contraction of 
the walls, but is mainly to be ascribed to a reflex stimulation of the 
vaso-dilator centre induced by the contraction of the abdominal ves- 
sels. The result is that while the outflow from all the vessels is re- 
tarded by digi toxin, the blood current in the splanchnic area alone is 
slower under strophanthin, while that in the limbs is actually accel- 
erated. 

It follows that under all of the series the blood tends to accumulate 
on the arterial side at the expense of the venous, for more blood is 

Fig. 43. 




iWiWi^^ 



Tracings of the blood-pressure and the volume of the leg and of the spleen of the dog under stro- 
phauthus. The volume of the leg increases with the blood-pressure, i. e., the vessels of the leg are 
dilated ; that of the spleen diminishes, i. e., the vessels are contracted ; 10 mg. of strophanthus were 
injected intravenously at a, followed by 5 mg. at b. (Gottlieb and Magnus.) 



pumped into the arteries and it has greater difficulty in escaping. But 
while under digitoxin the different regions of the body appear to be 
equally affected, strophanthin, digitalin and convallamarin not only 
tend to accumulate the blood on the arterial side, but divert it from 
the internal organs to the limbs. 

When the extreme slowing of the second stage appears, the output 
of the heart is reduced, and the pressure in the aorta and the velocity 
of the blood may become subnormal (Fig. 44). When the acceleration 
of the third stage follows, the output is again augmented and may be 
greater than ever ; the blood-pressure and velocity increase, but the heart 
soon becomes irregular in the force of its contractions, the output varies 
from second to second, and the pressure and velocity in the aorta falls 
slowly. The blood-pressure tracing shows the irregularity of the 
heart more or less accurately, but must not be taken to indicate at all 
the real condition of that organ, as the constriction of the arterioles 



THE DIGITALIS SERIES. 453 

varies at different times. E\ r entually the pressure falls to zero when 
the heart ceases. 

In the pulmonary circulation the pressure is not raised by some of 
the series such as strophanthin and helleborein, while after digitalis a 
very distinct rise in the pressure in the pulmonary artery is seen. Yet 
all of them increase the output of the right ventricle. The explana- 
tion of this paradox probably is that the pulmonary vessels can contain 
not only the ordinary supply of blood, but also an increased volume 
without offering any great resistance. If, however, the lumen of the 
pulmonary vessels be narrowed, as by digitalis, and an increased 
amount of blood must be accommodated at the same time, sufficient 
resistance is met with to augment the pressure in the pulmonary artery 
considerably. In the later stages the pulmonary circulation presents 
changes similar to those of the systemic. 

Action on the Renal Secretion. When digitalis was first introduced 
to the notice of the medical profession by Withering, its action on the 
heart was not appreciated. Withering used it only to remove accumu- 

Fig. 44, 

/i/WVWWWWW\ 




AHW/V'A^MwwwlH 




fiiiinii i mi in in mi iiiiiiiin nun nun n nn iini i iiiiin i i n muni Mini 

A B C D E 

Blood-pressure tracing under digitalis, ^.normal; B, therapeutic stage; C, excessive inhibition 

causing a low blood-pressure from lessened output of the heart. D, excessive inhibition with some 

irregularity in rhythm. E, third stage of irregularity, during which the blood-pressure rises again 

from the increased output of the heart and the further contraction of the vessels. 

lations of fluid from the body, which it accomplished by increasing the 
secretion of urine. This observation of Withering was soon confirmed 
by further experience in the use of this drug, but it was long dis- 
puted whether this diuretic action occurred in health, or whether it 
was not confined to cases in which pathological accumulations of fluid 
were present. Digitalis, however, as is now conceded by almost 
everyone, causes some increase in the quantity of urine secreted by the 
normal animal, although this is small compared with that in cases of 
dropsy. The fluid of the urine is much more largely augmented than 
the solids, which may remain unchanged. The cause of this increase 
in the renal secretion is not generally believed to be a direct action on 
the secretory epithelium- such as is met with under caffeine ; on the 



454 



ORGANIC DRUGS ACTING AFT Ell ABSORPTION. 



contrary, the kidneys themselves are supposed to be acted on only in- 
directly through the changes in the circulation. The renal vessels are 
contracted by the members of this series in the same way as the vi 
of the other abdominal organs (Gottlieb and Magnus), and this might Ik; 
expected to lessen the secretion of urine, for other agencies which con- 
tract the renal vessels have this effect. The diuresis induced by digi- 
talis must accordingly be ascribed to the cardiac changes and not to 
the vaso-constrictor action. It may be supposed that the accumulation 
of the blood in the arteries and the consequent fall of the venous pres- 
sure, which has been shown to occur, lead to an augmented flow of the 
lymph into the blood vessels, and that the blood is thus diluted and 

Fig. 45. 



D 



D 



A B D 

Diagram representing the secretion of urine in a rabbit under digitalis. Each rectangle represents 
the amount of urine secreted in ten minutes. A and B, normal secretion. In the next ten minutes 
a small dose of digitalis D was injected intravenously and a rapid increase in the secretion followed. 
At D' and D" further injections were made, each being succeeded by a considerably augmented 
flow of urine. The dotted line represents the average blood-pressure at each period. It will be ob- 
served that each injection is followed by some increase in the arterial tension. Contrast Fig. 23 (p. 
250) as to the amount of the secretion, and also as to the behavior of the blood-pressure. 

the kidneys therefore incited to abnormal activity, while at the same 
time their nutrition is improved ; and in addition, the increased pressure 
in the glomerulus must accelerate the filtration through the capsule. 
It is possible, also, that at any rate some of the members of this series 
act as slight irritants to the renal epithelium. The appearance of blood 
and albumin in the urine of animals after large doses of squills and 
digitalis certainly indicates some local action quite apart from the cir- 
culatory changes. 

Another organ which has been examined after the injection of digitalis 
is The Brain. It was supposed at one time that digitalis might induce 
anaemia of the brain from its prolonging the diastolic pause, and that 
in aortic regurgitation this might be of serious import. It has been 
demonstrated, however, that the brain is more largely supplied with 
blood under digitalis than under normal circumstances, provided that 
only therapeutic doses are used. 



THE DIGITALIS SERIES. 455 

The changes in the circulation in man can be followed only imper- 
fectly. The heart rhythm is very distinctly slower, and the apex beat 
is much stronger than before the administration of the drug ; the 
pulse is slower and stronger and the artery feels more tense. It must be 
added that the strength of the pulse is not to be regarded as a gauge 
of the changes in the cardiac muscle, for it is due not only to the in- 
creased strength of the cardiac contraction but also to its slow rhythm. 
When the heart is beating rapidly, the arteries have no time to empty 
themselves completely, and the pulse is small, while on the other 
hand, when digitalis slows the heart, the arteries have time to empty 
their contents into the capillaries before the next contraction occurs, 
the walls therefore become more flaccid, and a new wave of blood 
causes a more distinct impulse. In some cases of fever the vagus 
seems to have less control over the heart than usual, and after digi- 
talis there is no very marked slowing, although the action on the car- 
diac muscle may be fully developed. The pulse is harder owing to 
the increased blood-pressure, but it is not much slower, and the im- 
pulse does not seem stronger than before. If the physician, judging 
from the pulse that the drug has been given in too small quantities, 
prescribes larger doses, the effects on the heart may be disastrous, as 
the third stage of irregularity and less perfect action of the heart may 
be induced. In those cases in which this series seems to have no action 
on the pulse, the heart and the general condition of the circulation must 
be very carefully examined before larger quantities are prescribed. 
If, for example, the urine be found increased, or the oedema is less 
marked than before, or the breathlessness and the dyspnoea have dis- 
appeared, the drug is fulfilling its chief purpose, even though the 
pulse remains apparently unchanged. 

In Cases of Poisoning with the digitalis series, the most alarming 
symptoms arise from the circulatory changes. In the well-known 
case of Koppe, who accidentally poisoned himself in the course of his 
investigations on digitoxin, the first symptoms were uneasiness, giddi- 
ness, nausea and vomiting, and great muscular weakness. The pulse 
then fell to about half its normal rate and became intermittent, and 
the increasing muscular weakness was accompanied by precordial 
anxiety, imperfect vision, and constant nausea and vomiting, which 
prevented sleep and rest, and which persisted for over thirty-six hours 
without improvement. The symptoms then slowly disappeared and he 
recovered entirely in about a week. The quantity taken by him was 
2 mg. (3L- gr.), but four days previously he had taken 1 mg. ( g L gr.), 
and it is possible that this may not have been absorbed completely. 
In any case the small dose of digitoxin necessary to induce almost 
fatal symptoms indicates that it is one of the most powerful poisons 
known at present. 

The main action of this series is on the circulation, but some other 
results of their administration of less consequence have been observed. 
Thus in fever the Temperature is not infrequently reduced, although 
it remains unchanged after the administration of digitalis to the normal 



456 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

animal. This action is said by some to be the result of collapse, while 
others believe it to be due to the changes in the circulation, but 
neither of these seems to be a very happy explanation. It lias been 
stated already that the members of this series act as stimulants to 
some parts of the central nervous system, and a possible explanation 
of their antipyretic action would be an increased activity of the temper- 
ature-controlling centre. It has been shown by Harnack that several 
central nervous stimulants, including picrotoxin, cause a fall in the 
temperature in this way. 

Another observation which has been made in regard to this series is that 
it tends to weaken and eventually to paralyze the Muscles, and still more, 
the terminations of the peripheral Nerves of the frog. For this purpose it 
has to be applied in quantities which would at once stop the mammalian 
heart, and this action certainly never even commences in warm-blooded an- 
imals. Large quantities of digitalis are said to act on the unstriated muscle 
of several organs, such as the stomach and uterus, and to increase their 
movements. 

PREPARATIONS. 

Digitalis (U. S. P.), Digitalis Folia (B. P.), foxglove, the leaves of Digitalis 
purpurea collected from plants of the second year's growth. 0.03-0.1 G. 
(-1-2 grs.). 

Extraclum Digitalis (U. S. P.), 10-20 mg. {\~l gi\). 

Extractum Digitalis Eluidum (U. S. P.), 0.05-0.1 c.c. (1-2 mins.). 

Infusum Digitalis, U. S. P., 4-8 c.c. (1-2 fl. dr.); B. P., 2-4 fl. drs. 

Tinctura Digitalis (U. S. P., B. P.), 0.3-1 c.c. (5-15 mins.). 

f ' Digitaline ' ' of commerce varies much in composition and in dose, some- 
times proving entirely inert, while at other times it has proved poisonous in 
comparatively small quantities. Crystalline digitaline very often consists 
largely of digitonin, which is entirely devoid of the digitalin action. Other 
preparations seem to contain much digitophyllin. u Digitalinum verum " is 
said to be pure digitalin, and may be injected subcutaneously without dan- 
ger. 2 6mg. GWogr-)- 

Digitoxin has been prescribed in doses of T V mg. (7A0 gr.), but the forms at 
present on the market vary greatly in strength. 

The tincture and infusion are the most commonly used preparations. 
The extract and the powdered leaves may be given in the form of pills. The 
preparations ought to be freshly made, and solutions of " digitaline " and digi- 
toxin must not be kept, as they soon decompose and become entirely inert. 

Strophanthus (TJ. S. P.), the seeds of Strophantus hispidus. 

Strophanthi Semina (B. P.), the seeds of Strophanthus Kombe. 

Extractum Strophanthi (B. P.), \—\ gr. 

Tinctura Strophanthi (TJ. S. P., B. P.), 0.3-1.0 c.c. (5-15 mins.). 
Strophanthin (non-pharmacopceial) varies in composition and in power. Its 
dose is generally given as 1 mg. (^ gr.), but this is often devoid of action, 
while in other cases 0.2 mg. has been found a sufficient dose, and it is 
therefore to be used with caution. Its solutions are very liable to decom- 
pose and have to be freshly prepared. 

Scilla (TJ. S. P., B. P.), squills, the bulb of Urginea maritima, Urginea 
Scilla, or Scilla maritima. deprived of its dry membranaceous outer scales 
and cut into thin slices. 0.05-0.2 G. (1-3 grs.) in pills. 

Acetum Scillse (TJ. S P., B. P.), 1-2 c.c. (15-30 mins.). 

Extractum Scillse Tluidum (TJ. S. P.), 0.05-0.1 c.c. (1-2 mins.). 

Tinctura Scillse (TJ. S. P., B. P.), 0.3-1 c.c. (5-15 mins.). 

Syrupus SciLLiE (U. S. P., B. P.), 2-4 c.c. (30-60 mins.). 



THE DIGITALIS SERIES. 457 

Syrupus Scill^: Compositus (U. S. P.), containing senega and tartar 
emetic, 0.5-2 c.c. (10-30 rains.). 

Oxymel Scillse (B. P.), J-l fl. dr. 

Pilula Scillse Composita (B. P.), contains ginger and ammoniacum, 4-8 grs. 

Piltjla Ipecacuanha cum Scilla (B. P.), contains 5 per cent, opium. 
4-8 grs. 

Squills is often prescribed in pill form as a diuretic ; as an expectorant 
the syrup is more often used. The compound syrup, U. S. P., or the pill of 
Ipecac and Squill, B. P., may be ordered instead of a cough mixture, as 
they contain the chief constituents of such remedies. 

Scillitoxin, etc. , of commerce are merely purified extracts and not pure 
principles. 

Apocynum (U. S. P.), Canadian hemp, the root of Apocynum cannabi- 
num. 

Extractum Apocyni Fluidum (IT. S. P.), 0.3-1 c.c. (5—15 mins.). 

Convallaria (U. S. P.), Lily of the Valley, the rhizome and roots of 
Convallaria majalis. 

Extractum Convallarise Fluidum (U. S. P.), 0.3-1 c.c. (5-15 mins.). 

Euonymus (U. S. P.), Euonymi Cortex (B. P.), Wahoo, the bark of the 
roots of Euonymus atropurpureus. 

Extractum Euonymi (U. S. P.), 0.05-0.2 G. (1-3 grs.). 
Extractum Euonymi Siccum (B. P.), 1-2 grs. 

Therapeutic Uses. — The chief purpose for which this series is used 
in therapeutics is to counteract certain changes in the circulation, which 
result in the blood accumulating in the veins in too large quantities, 
while the arteries are less completely filled than usual. And first of 
all, in cases of dilatation of the heart with a weak and insufficient 
systole, its action is almost specific. This is true whether one or both 
ventricular chambers are affected, as long as the cardiac muscle itself 
has not undergone degeneration. In these cases the action is very 
simple — the increased ventricular systole approaches the normal, the 
output of the heart is increased, and in some cases at any rate, the 
dilatation is diminished by the direct action of the drug. The effect 
is an increased velocity and pressure in the arteries, and an improved 
nutrition of the whole body. The organ which suffers most of all 
under the malnutrition caused by dilatation of the chambers is the 
heart itself, and, accordingly, in these cases the heart is found better 
nourished and has more of a tendency to hypertrophy after digitalis or 
its allies. Eventually the walls of the heart become so enlarged as to be 
able to carry on the work without the additional stimulation of digitalis, 
and the drug ought therefore to be stopped. It must be remembered that 
the hypertrophy of the heart is not a direct effect of this series, which 
only puts the organ in a condition in which it receives more nourish- 
ment and is therefore more likely to hypertrophy. The effects in 
these cases of dilatation seem to be attributable entirely to the action 
on the cardiac muscle. 

It is frequently stated that the slowing of the heart, which allows the heart 
more time to rest and more time to fill itself, is accountable for the improve- 
ment. But numerous other drugs slow the heart quite as much and in exactly 
the same way, yet are of no benefit but rather the reverse in those condi- 



458 ORGAN fC DRUGS ACTING AFTER ABSORPTION. 

tions in which digitalis is most valuable. Aconitine, for example, slows the 
heart by stimulating the vagus centre, but no one would dream of using 
aconite as a substitute for digitalis in dilatation of the ventricles. 

Another explanation of the action of digitalis in cardiac dilatation is that 
the vagus being the trophic nerve of the heart, its stimulation increases the 
tendency of the heart to hypertrophy, and this series therefore causes hyper- 
trophy by stimulation of the trophic nerve. Any explanation which requires 
the assumption of trophic nerves is fraught with danger, however, and this 
one is easily refuted by the fact that aconite does not induce hypertrophy of 
the heart. 

The true explanation of the action of digitalis is the action on the cardiac 
muscle, by which the systole is strengthened and the output of the heart is 
increased. 

Mitral incompetency may be taken as a concrete example of cardiac 
disease. Here some of the blood, instead of passing into the aorta 
during the ventricular systole, passes back into the auricle. In course of 
time the auricle dilates owing to the pressure during its diastole, and the 
consequence is that the lungs become congested, the right ventricle and 
eventually the right auricle dilate, and the whole systemic circulation 
is retarded. (Edema and dropsy follow, the kidneys and other organs 
become overfilled with blood, and the whole economy is thrown into 
disorder. The left ventricle is not affected directly by the pressure, 
but it suffers in the general malnutrition, and may become weak and 
dilated like the rest of the heart. If now one of this series be given, 
the right and left ventricles commence to beat more strongly, their out- 
put is increased, and the blood is forced through the lungs. It still 
regurgitates into the left auricle, but the proportion passing back to 
that driven forward is smaller, owing to the increase in systole, which 
lessens the mitral orifice. Moreover the right ventricle is able to over- 
come the pressure in the pulmonary artery, and therefore soon ceases to 
drive blood into the right auricle, and the systemic veins can pass their 
blood into the heart without difficulty. The congestion of the organs 
rapidly disappears, the kidneys become better nourished, and finding 
large quantities of fluid accumulated in the body, at once proceed to 
excrete it. The heart itself improves in condition, but more work is 
required of it than in the normal body, because some of its work is 
still lost through the blood passing backwards from the ventricle in- 
stead of forwards. The muscle responds to the strain by hypertrophy, 
and when this process is complete, the drugs have fulfilled their pur- 
pose, and further administration is useless and may be dangerous. 

The only action of the drug required here is the increased contraction 
of the ventricles and auricles in systole, and this is exactly the point 
in which this series differs from all others. At the same time, if the 
diastolic dilatation becomes less marked, as it does in many experi- 
ments on the normal heart, this must also aid in such a case, because 
the more dilated the ventricle, the less perfectly does the mitral valve 
close the auriculo-ventricular orifice at the beginning of systole. If 
then the dilatation of the heart becomes less, either from a direct action 
of the drug, or as a result of the improved nutrition of the muscle, the 
imperfection of the valve may be compensated for by the narrowing of 






THE DIGITALIS SERIES. 459> 

the orifice. If the muscular action predominates sufficiently over the 
inhibitory, a further factor may aid in repairing the breach of the valve, 
for the auricular muscle is acted on in the same way as the ventricu- 
lar — its contraction is more complete, and the auricle therefore emp- 
ties itself more perfectly, and contains less blood at the beginning of 
the ventricular systole than it otherwise would. If, in addition, the 
auricular relaxation is lessened by digitalis, a greater resistance must 
be offered to the regurgitating blood. The increased contraction of the 
papillary muscles may also aid in the therapeutic effect by closing the 
valves more completely. 

In aortic incompetency the same beneficial results may be expected, 
because here again there is more blood expelled into the aorta, and at 
a higher pressure. The less dilated ventricle also presents a greater 
resistance to the return of the blood. It is true that longer time is 
allowed for the blood to pass back into the ventricle owing to the pro- 
longation of the diastolic pause, but this does not seem to be sufficient 
to counterbalance the benefits of the more complete contraction of the 
ventricle. 

In narrowing of the orifices, the improvement observed after digi- 
talis may also be explained by the stronger and more complete con- 
traction of the ventricles. Stenosis very rarely occurs unaccompanied 
by regurgitation, however, and the diminution of the backward flow 
may be the main object attained by these drugs in this condition. 

On the right side of the heart the same action occurs as on the left, 
and in dilatation of the right ventricle, which often occurs as the result 
of pulmonary disease, this series acts by increasing the strength of the 
ventricular contraction. In these cases of cardiac dilatation resulting 
from pulmonary disease, it would seem that those of the series which 
have least effect on the pulmonary vessels ought to be the most bene- 
ficial. Strophanthus, as has been stated, acts as strongly on the heart, 
but much less strongly on the vessels than digitalis, and it might there- 
fore be expected that it would prove preferable to the latter in those 
cases. Whether this is correct or not can only be decided by clinical 
experience, and the point has not been investigated sufficiently to allow 
of a definite statement. 

In numerous acute febrile conditions the heart becomes affected, pos- 
sibly in part by the high temperature, but largely from the toxic prod- 
ucts circulating in the blood. The chief cardiac symptoms are dilata- 
tion with a weak systole and a small "fluttering" pulse. In these 
cases digitalis and other similar drugs may be of great service in slow- 
ing the accelerated heart, and in increasing the extent of systole, and 
thus improving the general circulation. In pneumonia more espe- 
cially, great improvement is often seen after digitalis. In this dis- 
ease besides the toxic action on the heart, there may be present more 
or less obstruction of the pulmonary vessels through pressure resulting 
in overwork and dilatation of the right heart. If this is a prominent 
factor, one might expect that strophanthus would be more beneficial 
than digitalis, while if the heart is directly affected by the high tern- 



460 ORGANIC DRUGS ACTING AFTER ABSORPTION 

perature and the toxines, digitalis would be preferable, owing to its 
increasing the tone of the arteries as well as the heart. The routine 
treatment of pneumonia with digitalis is often recommended, but is to 
be deprecated on the general principle that a drug is not to be pre- 
scribed until some special indication for it appears ; unless distinct 
evidence of circulatory disturbance is present, digitalis ought to be 
withheld. 

In acute fevers the inhibitory mechanism is often less irritable than 
normally, and the activity of the drug must not be estimated by the 
slowness of the pulse. (See page 455.) 

In some forms of dilatation of the heart digitalis and its allies are 
to be avoided. Thus where extensive degeneration of the heart mus- 
cle is present, as in fatty heart, little or no benefit from the muscular 
action is to be expected, for the muscle itself is too weak to respond to 
the stimulation. On the other hand, digitalis, by increasing the pressure 
against which the heart has to contract, may cause the most serious re- 
sults — the systole becomes even weaker than before its administration, 
and brain anaemia, syncope, and not infrequently sudden death follow. 
In other cases, while the condition of the heart is eminently suitable for 
digitalis treatment, disease of other parts of the body may preclude its 
use. Thus if extensive degeneration of the arterial coats is present, the 
increased pressure in the interior of the vessels may lead to rupture of 
their walls and apoplexy. In those cases, if any of the series is to be 
given, it ought to be strophanthus, which causes a less extensive rise 
in the blood-pressure than digitalis, and it is recommended that either 
be prescribed along with some drug to dilate the vessels and lessen 
the arterial tension, such as nitroglycerin or some other of the nitrite 
series. In treating with digitalis and a member of the nitrite series, it 
is found that the digitalis action sets in somewhat slowly, and persists 
for a long time, while the nitrites act rapidly, but are excreted com- 
paratively soon. The best results are therefore obtained by frequent 
small doses of nitroglycerin, which need not be administered for some 
hours after the first dose of digitalis. 

In some cases dilatation of the heart seems to be due, at any rate in 
part, to increased arterial tension from disease of the arterial walls and 
of the kidneys. In these cases digitalis is to be used with caution, 
because of its vaso-constrictor action, and perhaps strophanthus is to 
be preferred to digitalis, unless one of the nitrite series is associated 
with the latter. 

Valvular disease is not in itself an indication for digitalis, for the 
heart tends to undergo compensatory hypertrophy in favorable condi- 
tions without the use of any drug whatever, and digitalis is indicated 
only when no such compensation occurs. At the same time hyper- 
trophy of the heart is not a contra-indication, as is often stated, for a 
special strain may cause excessive dilatation in a hypertrophied heart, 
and digitalis may be necessary until a second hypertrophy has occurred 
and restored the equilibrium once more. 

Digitalis is often prescribed in tachycardia (rapid heart) in order to 



THE DIGITALIS SERIES. 46 L 

slow the rhythm only, but if no other symptoms than acceleration are- 
present, other drugs, such as aconite or strychnine, may be substituted 
for digitalis, and do not entail the other changes in the circulation. 

It has been mentioned that the exhibition of digitalis in fever is 
often followed by a fall of temperature, and Traube recommended it 
as an antipyretic, but it is no longer used for this purpose, as the 
modern antipyretics are much more powerful and certain in their 
action, and at the same time are less dangerous. 

The diuretic action of digitalis is also not advised except where 
other indications than a diminution of the renal secretion are present, 
for in ordinary cases it has much less effect than caffeine and other 
diuretics. If the anuria be secondary to disturbances of the circula- 
tion, however, digitalis is the diuretic par excellence and cannot be 
replaced by any of the ordinary means of promoting the urinary secre- 
tion, although they may advantageously be combined with it. Squills 
is more frequently used as a diuretic than digitalis, and it seems prob- 
able that in addition to its action on the heart and circulation, it exer- 
cises some direct stimulant influence on the renal epithelium. Squills 
and digitalis are often prescribed together, where large accumulations 
of fluid have to be removed. A famous pill used in these cases con- 
tains a grain each of digitalis, squills and calomel. 

Several of these drugs are of considerable benefit in pulmonary 
diseases accompanied by cough. Thus in bronchitis, more especially 
in cases of old standing, the addition of squills to an " expectorant 
mixture " is often followed by the most satisfactory results. The 
action here is probably two-fold. In the first place, the right heart 
may be dilated owing to the frequent strain put on it by coughing,, 
and squills remedies this condition by its usual cardiac action. In the 
second place, all these drugs possess to a certain extent emetic prop- 
erties, and thus cause an increase in the bronchial secretion, and ren- 
der the sputum less tenacious and more easily expectorated. The 
addition of squills, in which this property is more developed than in 
the others, has the same effect as the prescription of ipecacuanha, 
along with the further action on the heart. 

Digitalis is sometimes prescribed to stop haemorrhages, but though 
it constricts the vessels it accelerates the flow through them, and, as in 
the case of other haemostatics, the benefits arising from the treatment 
are problematical. 

Squills was at one time used as an emetic, but this cannot be recom- 
mended, owing to the danger of its absorption. Euonymus has been 
employed as a purgative more frequently than as a cardiac remedy. 
(See page 107.) 

Some conditions in which the cardiac action of this series is to be 
elicited only with the greatest caution, have been already indicated. 
A further danger, which attends the use of digitalis perhaps more 
than that of the rest of the series, is due to its Cumulative Action. 
For the first day or two after the exhibition of this drug, no effects 
may be noted in the pulse or general circulation ; the ordinary symp- 



462 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

toms are then produced, and if the drug be continued, remain fairly 
constant for some time. Sometimes much more marked symptoms of 
digitalis action appear suddenly, however, — the pulse becomes alarm- 
ingly slow and irregular, the patient complains of weakness and faint- 
ness, nausea and occasionally vomiting, in fact the symptoms of the 
second stage set in. This is known as cumulative action, and is prob- 
ably due to irregularities in the absorption and excretion or destruction 
of the poison. It is known that the absorption is slow, for 12-36 
hours may elapse before any effects follow the exhibition of the drug. 
On the other hand, the excretion or destruction must be equally slow, 
for the symptoms sometimes last for several days after it has been dis- 
continued. If then anything happens to disturb the equilibrium of 
absorption and excretion, if, for example, the excretion is slower than 
usual, or if any irritation of the stomach and intestines causes a more 
rapid absorption, the drug accumulates in the blood, and the same 
effect is produced as if a poisonous dose had been administered. In 
order to avoid this cumulative effect, the condition of the pulse must 
be carefully controlled, and as soon as the circulation shows any signs 
of excessive action, the drug ought to be discontinued for one or two 
days and resumed in smaller quantities. These cases of poisoning are 
not serious if observed in time. Some members of the series — stro- 
phantus and squills — are said not to be cumulative, but some doubt 
exists as to the truth of this assertion. 

Another disagreeable feature observed in the use of this series is the 
action on the stomach and intestine. As has been noted already, the 
local action may produce the usual symptoms of gastric irritability, 
and the patient suffers from loss of appetite, nausea and gastric dis- 
comfort, just when it is important that the nutrition should be the best 
attainable. Numerous attempts have therefore been made to obtain 
preparations which possess the cardiac without the local action. Some 
of these seem to be fairly free from irritant properties; for example, 
some of the digitalines can even be injected subcutaneously without 
giving rise to any irritation or inflammation. But unfortunately all 
those preparations vary so much in strength, even when prepared by 
the same method, that their use is scarcely to be recommended. At 
the same time, in cases where the ordinary pharmacopceial preparations 
cause marked gastric irritation, some of the so-called " pure principles " 
may be made use of with advantage. 

So little is known regarding the comparative action of the members 
of this series that the special indications for each individual are alto- 
gether indefinite. It is recognized that strophanthus acts less on the 
vessels than digitalis, and this gives an indication for its use in some 
cases. On the other hand, squills acts more on the kidneys than either, 
and is therefore given frequently as an adjuvant to digitalis in cases 
where diuresis is desired. It also irritates the gastric mucous mem- 
brane more, and is often used as an expectorant. But the details of 
the action of each are still to be worked out. One important question, 
which is practically unbroken ground, is the relative action of each on 



SUPRARENAL OR ADRENAL GLANDS. 463 

the vagus centre and on the heart. The beneficial results from the use 
of digitalis are, as has been pointed out already, to be ascribed almost 
entirely to its action on the cardiac muscle. The stimulation of the 
vagus may conceivably lessen the benefits of the cardiac action by 
weakening the auricular contraction and slowing the rhythm, so that 
it would be of considerable interest and importance to find a drug 
having the same cardiac action without the inhibitory, 1 and, failing in 
this, to compare the effects of digitalis alone with those of digitalis and 
a drug which weakens the inhibitory action. This would have to be 
given in quantities sufficient to prevent an increased inhibition without 
cutting off the normal restraining impulses which pass down the vagi, 
and the treatment would be rendered considerably more difficult. 

Bibliography. 

The bibliography on the digitalis series is so extensive that the student can only be 
referred to that given by the following authors. 

Boehm. Pfliiger' s Arch. f. d. ges. Physiol. , v. , p. 153. 

Schmiedeberg. Arch. f. exp. Path. u. Pharm., xvi., p. 149. 

Robert. Ibid., xxii., p. 77. 

Francois-Franck. Clinique medicale de la Charite. Paris, 1894, p. 549. 

Cushny. Journ. of Exp. Med., ii., p. 233. 

Harnack. Berl. klin. Woch., 1895, p. 759. (Erythrophlceine.) 

Marshall. Journ. of Physiol., xxii., p. 1. 

Pfaff. Arch. f. exp. Path. u. Pharm., xxxii., p. 1. 

Klingenberg. Ibid., xxxiii., p. 353. 

Goldenberg. Inaug. Diss., Dorpat, 1892. 

Jarmerstedt. Arch. f. exp. Path. u. Pharm., xi., p. 22. (Scilla. ) 

Cervello. Ibid., xv., p. 235. (Adonis.) 

Fraser. Trans. Koy. Soc. Edinburgh, 1890 and 1891. (Strophanthus. ) 

Fraser and Tillie. Arch, internat. de Pharmacodyn., v., p. 349. (Acokanthera. ) 

Prevost. Trav. du Lab. therapeut. exp., ii., p. 221. 

Lewin. Virchow's Arch., cxxxiv., p. 231 ; cxxxvi., p. 83; cxxxviii., p. 283. 

Kiliani. Arch, der Pharmacie, 1892-1899. 

Hedbom. Skandin. Arch. f. Phys., viii., p. 185. Arch. f. exp. Path., xlv., p. 317. 

Fraenkel. Arch. f. exp. Path. u. Pharm., xl., p. 40. 

Resh. Ibid., xliii., p. 130. 

Straub. Ibid., xlv., p. 317. 

Cloetta. Ibid., xlv., p. 435. 

Gottlieb, Sahli, etc. Verhand. d. Congress f. inn. Med., 1901. 

Feist. Ber. d. deutsch. chem. Gesell., 1900, p. 2063. (Strophanthin. ) 

Wybauw. Arch. f. exp. Path. u. Pharm., xliv., p. 434. 

Braun u. Mager. Sitzungsb. d. Wiener Akad. Math, naturwissen. CI. , cviii. , iii. , 
p. 471. 

Faust. Ueber Bufonin u. Bufotalin, Leipsig, 1902. 

Gottlieb and Magnus. Arch. f. exp. Path. u. Pharm., xlvii., p. 135. 

XXX. SUPRARENAL OR ADRENAL GLANDS. 

The suprarenal capsules of animals have recently been shown to 
contain a body which possesses a powerful action on the orgamsm, and 
which the glands normally secrete into the blood vessels. The active 
principle, Epinephrine 2 (C 10 H n NO 3 ), has been isolated by Abel and 
Crawford by a complicated process, and has proved to be a base which 

1 Helleborein has comparatively little action on the inhibition, but in a number of 
cases of cardiac disease in which I have attempted to substitute it for digitalis it induced 
irritation of the intestine and diarrhoea through its local irritant action. 

2 The bodies known as Suprarennin (Fiirth) and Adrenalin (Takamine and Aldrich) 
appear to be slightly modified epinephrine. 



464 



ORGANIC DRUGS ACTING AFTER ABSORPTION 



probably contains a pyrrhol or skatol nucleus, and is nearly related to 
the vegetable alkaloids ; epinephrine itself is so unstable that it is de- 
composed by attempts to isolate it, and though the salts are less easily 
changed, they also appear to undergo some alteration when kept for 
some time, for they become much less soluble. Comparatively few 
experiments have been done with the pure substance, but there is no 
question that it possesses the characteristic action of the extracts, 
though some results described as arising from these may be due to 
proteids or other impurities, such as choline and neurine. This active 
principle exists only in the medulla of the gland, and therefore does 
not represent the whole function of the organ in all probability. 



Fig. 46. 




Tracing of the blood-pressure under the influence of extract of suprarenal gland, which was in- 
jected into the jugular vein at a. 

In the frog, the suprarenal extract causes paralysis of the central 
nervous system, which is of only short duration, however, even when 
large quantities are injected. In mammals the hypodermic application 
of large doses is followed, as a general rule, by some excitement, agita- 
tion, and often tremors, although these are not marked in the rabbit ; 
vomiting has been observed by Gourfein in dogs. This stage is fol- 
lowed by paresis of the hind limbs, often by rapid respiration and 
dyspnoea, and eventually by failure of the respiration and death. In 
some animals the urine is increased in quantity, and haemorrhages 
occur from the mucous membranes and from the kidney. It is to be 
noted that only large quantities of the gland are fatal when they are 
injected hypodermically, and it may be doubted whether any symptoms 
can be produced when it is absorbed from the stomach and intestines. 
Abel states that a strong solution of epinephrine applied to the tongue 
induces partial anaesthesia, which may, perhaps, be due to the constric- 
tion of the vessels ; it possesses a weak bitter taste. 

On the other hand, comparatively small quantities elicit marked 
symptoms when they are injected into the blood vessels, these consist- 
ing in a very rapid and very pronounced rise of the blood-pressure, 
with slowing and strengthening of the heart beat. The action of the 



SUPRARENAL OR ADRENAL GLANDS. 465 

suprarenal extract injected into a vein is in short that of the members 
of the digitalis series. The slowness of the pulse is due to stimulation 
of the pneumogastric centre in the medulla oblongata, while the heart 
muscle is affected in the same way as by digitalis, that is, its systole is 
much strengthened and its diastole is often rendered less complete. 
The rise in the blood-pressure is due chiefly to a marked contraction 
of the peripheral arterioles from direct action on the muscular coats, 
in part to the increased efficiency of the cardiac contractions, perhaps 
in part to stimulation of the vaso-motor centre. 

The extract differs from the digitalis series chiefly in the rapidity 
with which these changes are elicited, in the rise of blood-pressure 
being greater, and in the action passing off more quickly. Mere traces 
of epinephrine are sufficient to cause this change in the blood-pressure 
when they are injected intravenously, while no distinct effect is pro- 
duced by much larger quantities injected subcutaneously or adminis- 
tered by the mouth. An explanation of this fact as well as of the 
short duration of the action may, perhaps, be found in the instability 
of the epinephrine ; the base itself, or some closely related product, 
has been found in the urine by Abel after its intravenous injection. 

Large quantities of the extract injected into a vein cause the same 
form of irregularity as the members of the digitalis series, and in one 
case fibrillary contraction of the heart has been observed from it. 
The frog's heart seems to be acted on less by suprarenal extract 
than the mammals', but Oliver and Schafer observed changes in it 
similar to those induced by digitalis. 

Some of the vessels do not seem to be influenced by it so much as 
others ; thus the pulmonary vessels are not narrowed at all or only 
very slightly, and even the direct application of the extract to the 
lungs does not cause pallor. The cerebral vessels also seem to undergo 
no constriction and in fact some evidence of their dilatation is pre- 
sented by the widening of the retinal vessels. This is due to the con- 
striction of the vessels in other parts of the body which diverts to the 
brain a larger amount of blood than usual. Gerhardt states that the 
vessels of muscle are scarcely changed in calibre, while those of the 
skin are contracted, but not in so marked degree as those of the abdom- 
inal organs. The constriction of the vessels of the stomach, intestine 
and other organs whose blood flow is regulated by the splanchnic 
nerve, is apparently the chief factor in the rise of blood-pressure, 
although the action is by no means confined to these. Even neighbor- 
ing organs vary considerably in their reactions ; for example, the 
uterine vessels are constricted while those of the bladder are much less 
affected. 

The contraction of the vessel walls may be demonstrated by perfus- 
ing blood containing epinephrine or the gland extract through the artery 
of an excised organ, for very much less blood escapes from the vein 
than when pure blood is used. Or a solution of the extract may be 
applied to the exposed mesentery, when the vessels are often entirely 
obliterated. The mucous membranes are similarly affected as is well 
30 



466 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

seen in irritation of the conjunctiva, for the redness and congestion 
give place to pallor when epinephrine .solution is applied, it has no 
effect on the unbroken skin, through which it is unable to penetrate to 
the vessels, but denuded surfaces become pale and anaemic under its 
influence and hemorrhages cease from the smaller vessels and capil- 
laries. 

In addition to the vessels a number of other forms of unstriatcd 
muscle are thrown into a condition of spasmodic contraction by supra- 
renal extract. Thus the muscular fibres of the eye that are innervated 
from the superior cervical ganglion undergo c ontrac tion when the drug 
is injected intravenously or applied locally. This results in dilatation 
of the pupil, withdrawal of the nictitating membrane, separation of the 
eyelids and protrusion of the eyeball, exactly as after cocaine or stimu- 
lation of the cervical sympathetic. The suprarenal extract differs 
from cocaine, however, in inducing those effects by acting directly on 
the muscle fibres and not on the nerve ends, for these changes can be 
elicited after complete degeneration of the nerve terminations. The 
muscle fibres supplied by the third nerve are unaffected. The con- 
traction of some involuntary muscles is inhibited by suprarenal 
extract, so that the cardiac sphincter of the stomach and the internal 
anal sphincter relax, and the movements of the stomach, intestine and 
bladder are retarded or altogether arrested. The uterus, vagina, vas 
deferens, seminal vesicles and the external genital organs are all con- 
tracted and anaemic in contrast to the relaxed condition of the stomach 
and intestine. 

The secretion of the salivary glands and of the raucous glands of the 
mouth and throat are increased, apparently through stimulation of the 
nerve terminations, asunder pilocarpine. The secretion is arrested by 
atropine, but can be reinstated by larger amounts of suprarenal extract 
which is a more powerful antagonist to atropine than pilocarpine. 
The lachrymal glands and the bile are also increased, while the secre- 
tion of the pancreatic juice and of the sweat is probably unchanged. 

Suprarenal extract injected hypodermically induces glycosuria, 
apparently through altering the activity of the liver and pancreas, 
for the sugar of the blood is considerably increased. 

Preparations. — No preparation of the suprarenal bodies is pharma- 
copoeial as yet. Occasionally the fresh gland is used, but as a general 
rule the gland dried and powdered, or a dry extract is preferred ; tab- 
lets may be made from these and dissolved in water when necessary. 
The active constituent is not decomposed by boiling, and the solution 
may be sterilized. It is important to remember that the solution 
rapidly deteriorates on keeping, so that it must be freshly made when 
its full activity is required. A very active preparation has been put 
on the market under the name of adrenalin, which appears to be a slightly 
altered epinephrine ; a solution of one part of adrenalin in one thou- 
sand to ten thousand of water has many advantages over the ordinary 
gland extracts. 

Therapeutic Uses. — Disease of the suprarenal gland leads to a series 



SUPRARENAL OR ADREXAL GLAXDS. 467 

of svmptoms known as Addison's disease, and it has been supposed 
that the extract of the gland might counteract this condition by sup- 
plying the substance whose deficiency induced the symptoms. As a 
matter of fact, however, but little success has attended its use for this 
purpose, and the failure may perhaps be due to the method of applica- 
tion, for it has been shown repeatedly that the characteristic effects of 
epinephrine cannot be elicited by its administration by the mouth or 
subcutaneously. It is possible that the extract might prove beneficial 
if it could be brought into the blood directly but this is quite impos- 
sible in a chronic condition such as Addison's disease. Its general action 
on the circulation might be taken advantage of in such emergencies as 
heart failure under anaesthesia or syncope, and in fact Gottlieb has 
shown that in animals poisoned with chloral or chloroform until the 
pulse has almost completely ceased, the circulation may be restored 
immediately by suprarenal extract. In order to elicit this action, the 
drug would have to be injected intravenously and little danger is to 
be apprehended from small doses if one can judge from the results in 
animals ; no such treatment has yet been adopted in man. 

The great use of suprarenal preparations is however due to its local 
effects ou the vessels. No other body is known which induces such com- 
plete contraction of the vessels in any part to which it is applied, and 
in addition suprarenal extract has only local effects, for it is oxidized so 
rapidly in the tissues that it has no general effect unless injected into the 
blood. Complete bloodlessness of a part may thus be elicited without 
alteration of the general blood-pressure and in fact without any appreci- 
able effect upon other parts of the body. This local ischaernia has been 
largely employed to allow of bloodless operations on the eye and to re- 
move congestion of the conjunctiva from various causes. It is often ad- 
ministered with cocaine in operations on the eye (1—6 per cent, solution 
of dried extract). In congestion of the nasal mucous membrane and 
in operations on the nose it is also used extensively and with much 
success. It may be sprayed into the nose in the form of a ten per 
cent, solution, or cotton soaked in this solution may be packed into 
the cavity. In epistaxis and in operations on the nose, the haemor- 
rhage ceases almost completely and the contraction of the mucous 
membrane permits of a clearer view of the field of operation. Hay 
fever is often relieved by similar treatment with suprarenal prepara- 
tions. A 10—20 per cent, solution of the dried gland has been found 
useful in haemorrhage from the ear, mouth and throat. 

Grunbaum first suggested its use in gastric haemorrhage, 5-10 
grains of extract being dissolved in water and swallowed ; the action 
is confined to the mucous membrane of the stomach. Similarly it may 
be injected into the rectum, bladder and uterus in congestion or haem- 
orrhage from these organs, and Schafer recommends it especially in 
post-partum haemorrhage, in which it acts not only on the uterine ves- 
sels but also on the muscular walls and arrests the bleeding by causing 
a tonic contraction. In all of these cases the suprarenal preparation 
has to be applied directly to the bleeding organ ; and no effects will 



468 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

follow from its being carried to them by the circulation. The local 
contraction of the vessels lasts very much longer than that induced by 
intravenous injection, for even dilute solutions induce ischaemia lasting 
from thirty minutes to two hours according to the rapidity with which 
the extract is absorbed. 

Bibliography. 

Oliver and Schcifer. Jour, of Phys., xviii., p. 230. Brit. Med. Journ., 1901, i., n 
1009. 

Szymonowicz. Pfi tiger's Arch., lxiv., p. 97. 

Rates. New York Medical Journ., lxiii., p. 647. 

Gourfein. Trav. du Lab. de Therapeutique experiment, de Geneve, ii., p. 128. 
Vincent, Journ. of Phys., xxii., pp. Ill and 270. 

Rardier. Arch, de Phys. (5), x., p. 370. Jour, de Physiol., i., p. 9o0. 

Gottlieb. Arch. f. exp. Path. u. Pharrn., xxxviii., p. 99. 

Abel. Ztschr. f. phys. Chem., xxviii., p. 318. Johns Hopkins Hospital Bulletin, 
July, 1897 ; Nov., 1901 ; Feb., 1902. 

JLewandowsky. Arch. f. [Anat. u.] Phys., 1899, p. 360. 

Roruttau. Pfliigers Arch., lxxviii., p. 97. 

Howell, Adami, Kinnicutt. Transactions of the Congress of Amer. Physic, and 
Surg., iv. 

Gerhardt. Arch. f. exp. Path. u. Pharrn., xliv., p. 161. 

Langley. Journ. of Physiol., xxvii., p. 237. 

Richards. Medical News, Feb. 1, 1902. 

Griinbaum. Brit. Med. Journ., 1900, ii., p. 1307. 

XXXI. THE NITRITES. 

The nitrites would naturally fall among the inorganic salts, but they 
act chiefly upon the circulation, so that it is convenient to place them 
near the digitalis series. 

Those which have been examined more carefully are the Nitrite of 
Sodium, and the Nitrous Ethers of the methane series, especially the 
Nitrite of Amy I, which is largely used in therapeutics. In these com- 
pounds the radicle — NO is attached to the metal or alkyl through 
an atom of oxygen, the formulae being K — O — NO, CH 3 — O — NO, 
C 3 H 7 — O — NO, C 5 H n — O — NO, etc., and the chief constituent is the 
O — NO, the metal or radicle being of less importance. A closely 
allied series of bodies are the nitrates, in which the nitrogen has five 
affinities and is connected again to the metal or radicle by oxygen, 
K— O — N0 2 , CH 3 — O — N0 2 , C 5 H n — O— N0 2 ,etc. Themetallic 
nitrates differ entirely from the nitrites in their effects and will be dis- 
cussed along with the other inorganic salts. Some of the Nitric Ethers, 
however, undergo a reduction when brought into contact with organic 
matter, and nitrites are thus formed, so that these bodies have effects 
very similar to those of the true nitrites, and have to be discussed 
along with them. The best known of such nitrates is the so-called 
Nitroglycerin, which is really the trinitrate of glycerin, (CH 2 (ON0 2 )- 
CH(ON0 2 )CH 2 (ON0 2 )), and is broken up by alkalies into a mixture 
of nitrates and nitrites. The nitrates have practically no action in the 
small quantities given, so that almost all the effects of nitroglycerin 
are due to the nitrite formed. 1 Many other organic nitrates also form 

1 Some doubt has been expressed of late years as to whether this reduction to nitrite 
really occurs in the tissues, and some grounds exist for the belief that nitroglycerin acts, 
as such (Marshall). 



THE NITRITES. 469 

nitrites in the tissues, but none of them with such rapidity as nitro- 
glycerin. 

Two which have been used to some extent in the last few years are solids 
— Erythrol Tetranitrate and Mannitol Hexanitrate. They act much more 
slowly and for a longer time than nitroglycerin. 

Another series of bodies which may be mentioned as occasionally acting 
like nitrites, although more feebly, are the nitro-bodies. In these the nitro- 
gen is attached to the alkyl directly, and not through the intervention of an 

H 
oxvgen atom. Examples of these are Nitromethane, HC — ]SO.,, and Nitro- 

H H 

ethane, CH 3 — C — X0 . Their action is so feeble as to preclude their use in 

H 
therapeutics, and seems due to the — NO a being split off in the tissues and 
reduced to nitrites in very small quantity. 

The best known member of the group is Amyl Nitrite, and its action 
will first be described, while the points in which the effects of the 
other members diverge from it will be discussed later. 

The characteristic results of the absorption of amyl nitrite are dila- 
tation of the vessels and the formation of methsetnoglobin. 

Symptoms. — After the inhalation of a few drops of amyl nitrite, the 
face becomes flushed, and the patient complains of a feeling of fulness 
and throbbing in the head. Some headache and confusion is often pre- 

Fig. 47. 



Tracing of the blood-pressure in the rabbit under amyl nitrite. From A to B, the blood-pressure is 
the normal. At B the inhalation was begun and the disturbance of the respiration is reflected in the 
blood-pressure tracing. Immediately afterwards the blood-pressure begins to fall and continues to do 
so even after the inhalation ceased at C. Note that the rhythm and strength of the pulse are compar- 
atively little altered. 

sent, the pulse is accelerated, and the respiration is somewhat quicker 
and deeper. The flush is often confined to the face and neck, but some- 
times spreads over the whole trunk, and passes off in a few minutes, 
unless the inhalation is continued. If large quantities of the drug be 
inhaled at once, however, or if the inhalation be continued for some 
time, a feeling of giddiness, weakness and eventually stupor follow, 
the pulse becomes slow, while the respiration still remains accelerated, 
but is shallower and often somewhat irregular; convulsive movements 
may occur, but in general large quantities may be taken without actual 
danger in the human subject. The blood is said to have assumed a 
dark color in some cases, but this seems to be rare. 

Action: Circulation. — In experiments on animals, the flushing and 



470 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

dilatation of the arterioles of the head is found to be accompanied and 
followed by a profound fall in the blood-pressure. The heart is accel- 
erated at the same time, and seems not to be responsible for the change. 
The cause, as has been repeatedly demonstrated, is the dilatation of 
the peripheral vessels, both arterioles and veins widening very consid- 
erably under the influence of the drug; the vessels of the abdominal 
organs and the brain are more affected than those of the extremities. 
This widening of the vessels might be produced either by depression 
of the vaso-constrictor centre, or by depression of the nerve ends and 
muscle of the arterioles and as a matter of fact each of these explana- 
tions has had its supporters, but the latter is now almost universally 
held to be the correct one. Stimulation of a constrictor nerve such as 
the splanchnic still produces some rise in the blood-pressure, so that 
the nerve terminations seem to be intact, and the seat of action of amyl 
nitrite is therefore held to be the unstriated muscle of the arteries and 
veins. No satisfactory explanation has been offered for the fact that 
in the skin only the vessels of the head and neck should be dilated, 
but other facts seem to indicate that these vessels occupy an exceptional 
position as regards their innervation and their reactions to drugs. 
Darwin was the first to point out that the blush of amyl nitrite corre- 
sponds in extent with the blush produced by emotion. Even in the 
frog the arterioles of the tongue are said to dilate more than those of the 
mesentery and the web after the application of amyl nitrite. The vaso- 
constrictor centre is often said to be depressed by amyl nitrite, and 
this may possibly be true, though this central action must be quite in- 
significant compared with that on the arterial walls, and has never 
been demonstrated even by the most careful and ingenious methods of 
experimentation. The direct action on the vessel walls may be easily 
shown by passing blood into the artery of the amputated extremity of 
an animal, and measuring the amount coming from the vein. If a few 
drops of amyl nitrite be added to the perfused blood, the outflow from 
the vein is greatly increased, although here no nervous mechanism can 
be concerned. 

The acceleration of the pulse is more marked in man and the dog 
than in other animals, and seems due to a depression of the inhibitory 
centre in the medulla oblongata, though several authors consider that 
a feeble direct action on the heart is also present. In the frog, as a 
general rule, no acceleration is caused by amyl nitrite, because there is 
no constant vagus tone in these animals. 

Large quantities of amyl nitrite slow and weaken the contractions 
of the heart, owing to a direct depressing action on the muscle. In 
the frog, the heart is usually slowed from the beginning of the appli- 
cation. 

The Respiration is generally accelerated, and at the same time ren- 
dered deeper by amyl nitrite. Not infrequently the breath is held at 
first, owing to a reflex from the nasal mucous membrane, but this is 
not so marked as in the inhalation of more irritant vapors, such as 
chloroform or ether. The acceleration seems due to a direct action on 



THE NITRITES. 



471 



Fig. 48. 



WWMwJ w h 




the respiratory centre in the medulla. After long inhalation, the res- 
piration becomes slower and shallower from depression of the centre, 
and in animals death occurs from its complete paralysis. 

The Kidneys are not much affected by this series ; occasionally a 
slight increase in the urine is observed, at other times a decrease, and 
after large quantities anuria may occur. The changes are evidently 
due to the changes in the calibre of the renal vessels. A small quan- 
tity may widen them when they are too contracted to allow of the 
maximal secretion, while on the other hand, if the normal calibre is 
the optimal, a nitrite may lessen the secretion by lowering the general 
blood-pressure. When large quantities lower the pressure, they in- 
evitably lead to a lessened activity of the renal epithelium, which may 
result in complete anuria. 

Small quantities of amyl nitrite seem to have no action whatsoever on 
the higher parts of the Central Nervous System. 
The throbbing in the head and slight confusion 
are evidently due to the dilatation of the ves- 
sels, in which the brain circulation is involved 
as well as that of the rest of the body. The 
sight is curiously affected in some people, for 
when a dark object on a white background is 
looked at, it seems surrounded by a yellow 
ring and that again by a blue one. In the 
beginning the medullary centres may be acted 
on reflexly from irritation of the nasal sensory 
terminations ; the respiration is inhibited, while 
the blood-pressure may rise and the heart be 
slowed from reflex action on the inhibitory and 
vaso-constrictor centres respectively. After- 
wards, the respiratory centre seems to be stim- 
ulated, the inhibitory is depressed, while the 
vaso-motor is practically unaffected. The spinal 
cord is not acted on in mammals, but is de- 
pressed in the frog. 

After larger quantities convulsions are often 
observed ; these seem to be of cerebral origin, 
and are probably due to direct action on the 
nerve cells, and not to the circulatory changes, although some authors 
attribute them to anaemia of the brain. 

The Peripheral Nerves and the Muscles are unaffected by the inhala- 
tion of amyl nitrite, but when the frog's muscles are exposed to the 
direct action of the vapor, they undergo a slow passive shortening and 
rigor, and on periodical stimulation the contractions become rapidly 
weaker, until finally no response is made to the electric shock. In- 
voluntary muscle is more easily affected than striated fibres, as has 
been shown by the behavior of the intestine and ureters, but even these 
seem less readily paralyzed than the muscle of the vessel walls, the de- 
pression and paralysis of which lead to the fall in the arterial tension, 



Blood-pressure under amyl ni- 
trite taken on a very slow drum 
in order to demonstrate the re- 
covery. The whole tracing oc- 
cupied some six minutes. The 
rapid fall of pressure is followed 
by an almost equally rapid re- 
turn to normal. (Cash & Dusr- 

STAN. ) 



472 ORGANIC DRUGS ACTING AFTER ABSORPTION 

as has been already stated. The nerve terminations seem to be un- 
affected even by very large quantities, so that as long as a contraction 
of the muscles can be elicited by direct stimulation, it follows also on 
stimulation of the motor nerve, and the vagus terminations in the heart 
can transmit impulses as long as the heart continues to beat. The 
Temperature is somewhat lowered by the nitrite series, owing to the 
dilatation of the skin vessels, but this fall is very insignificant. 

Amyl nitrite causes the Blood to assume a dark chocolate color, 
both in the body and in the test-tube. The color is due not to any 
compound formed by the nitrites, but to their changing the haemoglo- 
bin to methaemoglobin and nitric-oxide-haemoglobin compounds in which 
the oxygen is attached much more firmly than in oxyhemoglobin, and 
which differ from it in the absorption bands seen in the spectrum. 
This change in the haemoglobin does not entail the destruction of the 
red corpuscles, and the compounds are eventually reduced by the tissues, 
although the reduction progresses much more slowly than that of ordi- 
nary oxy haemoglobin. In man, usually very little of the haemoglobin 
is thus transformed, and even after large quantities have been inhaled 
no abnormal coloration of the blood is noticeable, but it has been de- 
monstrated recently that the alteration of the haemoglobin is the cause 
of death in some animals, through the blood becoming incapable of 
carrying oxygen to the tissues. If, however, asphyxia be prevented 
by the inhalation of oxygen under pressure, the tissues themselves are 
eventually acted on. The formation of methaemoglobin does not seem 
to bear any relation to the action of the nitrites on the vessel walls. 

Excretion. — After absorption into the blood, amyl nitrite seems to 
break up with the formation of nitrites of the alkalies. These undergo 
partial oxidation and appear in the urine in the form of nitrates and 
nitrites, but the quantity of these excreted is never equal to the nitrite 
absorbed, so that it seems probable that some part undergoes still fur- 
ther change and appears as one of the normal excretions. The amyl 
disappears, and is probably oxidized completely, although some may 
appear in the breath. 

Nitrite of amyl given by the stomach is very much less active than 
when inhaled, as the nitrous acid is freed by the gastric juice and im- 
mediately decomposes. When injected subcutaneously it acts much 
more slowly and weakly than when absorbed by the lungs, and gen- 
erally gives rise to glycosuria and slight diuresis. No satisfactory 
explanation of this fact has been given, but it is possible that the 
formation of methaemoglobin may cause partial asphyxiation of the 
tissues, and thus cause the formation of excess of lactic acid and gly- 
cosuria. 

The pharmacopoeial amyl nitrite, with which most of the experi- 
ments have been performed on which the above description is based, 
is not a pure substance,' but consists of the nitrites of two different 
amyls — a-amyl and /?-amyl — along with isobutyl, ethyl, and propyl 
nitrites. A number of the pure nitrites have been examined by Cash 
and Dunstan, who find that in general features they resemble each 



THE NITRITES. 473 

other closely. The more unstable the compound, the more rapidly 
does the fall in blood-pressure occur, while the less easily decomposed 
compounds are somewhat slower in their action, but cause depression 
of the blood-pressure for a much longer time. The acceleration of 
the heart and the extent of the rigor produced in the frog's muscle de- 
pend also on the rapidity of the disintegration of the nitrite compound, 
and therefore are parallel to the fall in the blood-pressure. 

The Nitrites of Potassium and Sodium act very similarly to those of 
the alkyls. They seem to have a more powerful action on muscular 
tissue, however, at any rate in the frog, for the muscles are paralyzed 
before the spinal cord, while after amyl nitrate the reverse is the case. 
They are administered by the stomach, and therefore act more slowly 
than amyl nitrite, but their effects last much longer. The gastric juice 
liberates part of the nitrous acid before absorption can occur, and it is 
immediately decomposed and often causes some eructation. The nitric 
acid formed from it may also give rise to irritation of the gastroin- 
testinal mucous membrane. The nitrite absorbed is excreted as nitrate 

Fig. 49. 

fi 10 20 30 40 50 1 hr. 2 hrs. , _ 2% hrs. 



Diagram to illustrate the intensity and duration of the action of the members of the nitrite series. 
The extent of the fall of pressure is measured along the vertical, the duration along the horizontal 
line. A, amyl nitrite, ethyl nitrite, etc.; B, nitroglycerin ; C, sodium nitrite ; D, erythrol tetranitrate. 
The greatest reduction occurs in A, but it passes off for the most part in 5 minutes and entirely in 20. 
Nitroglycerin acts more rapidly than the last two, and its effects continue almost as long as those of 
sodium nitrite. Erythrol tetranitrate only exerts its full effect after the action of the others has 
passed off. (After Bradbury.) 

in the urine, although some of it may remain unoxidized. The metal- 
lic nitrites do not as a rule cause so much headache and flushing of 
the face and neck as the alkyl compounds. 

Nitroglycerin produces the same effects as the other members of 
this series, but acts much more powerfully than either the metallic or 
alkyl nitrites. It presents some minor points of difference, as in pro- 
ducing convulsions in the frog and in some mammals when given in 
very large quantities, and in causing more severe headache in man. It 
is not decomposed in the stomach, but on reaching an alkaline fluid, 
such as the blood, at once breaks up into glycerin, nitrites and nitrates, 
in the proportion of two parts of the former salt to one of the latter. 
Its action commences very soon after its administration, and lasts 
much longer than that of amyl nitrite. The explanation of its greater 
activity may be that it is absorbed unchanged, but is then broken 
up at once, while the metallic nitrites are decomposed in the stomach 
and much of the nitrous acid is lost. 

The convulsions are probably due to the Avhole molecule of nitro- 



474 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

glycerin, which may perhaps be decomposed more slowly in some 
animals than in others. Nitroglycerin is not wholly broken up in 
the human body, however, for it has been found in the urine, and the 
headache which so frequently follows its administration in man, has 
been ascribed to the undecomposed molecule, and not to the nitrite 
constituent. It is generally supposed to be extremely poisonous, 
and is prescribed in exceedingly minute doses, but it has been shown 
that while very small quantities are sufficient to produce therapeutic 
effects in man, the toxic dose is enormous in animals. 

Several other organic nitrates have also been found to reduce the 
blood-pressure, and to cause the formation of methsenioglobin, but their 
decomposition proceeds much more slowly than that of nitroglycerin, 
and they have not been much used in therapeutics. Erythrol tetrani- 
trate and mannitol hexanitrate act more slowly, and the fall of pres- 
sure is more gradual, and lasts longer than under any others of the 
series. 

Preparations. 

Amyl Nitris (U. S. P., B. P.), a yellow, very volatile fluid, with a strong, 
fruity odor, soluble in alcohol and ether, but rapidly decomposed by water. 
2-5 drops are poured on a handkerchief and inhaled. A convenient prepa- 
ration is the amyl nitrite ' ' pearls, ' ' which are thin glass capsules, each con- 
taining a dose of the remedy, and one of which is broken in the hand- 
kerchief when necessary. Amyl nitrite is liable to decompose when kept 
long, and ought to be used only when recently prepared. 

Spiritus Glonoini (U. S. P.), Liquor Trinitrini (B. P.), is a one per 
cent, alcoholic solution of nitroglycerin. 0.03-0.1 c.c. ($-2 mins.). 

TabellvE Trinitrini (B. P.), or nitroglycerin tablets, are formed of 
chocolate, and contain each T ^ gr. of nitroglycerin. 1-2 tablets. 

Liquor Ethyl Nitritis (B. P.), a solution in alcohol and glycerin of ethyl 
nitrite* (2^-3 per cent.), forming a limpid liquid of apple-like odor and taste. 
20-60 mins. 

Sodii Nitris (U. S. P., B. P.) (NaN0 2 ), 0.05-0.1 G. (1-2 grs.). It may be 
prescribed in tablets or in solution. 

Spiritus ^Etheris Nitrosi (U. S. P., B. P.), sweet spirits of nitre, con- 
tains only traces of ethyl nitrite, along with ether and aldehyde in alcoholic 
solution. When freshly prepared it acts like the other nitrites, but when 
prescribed along with water, as is usually the case, the nitrite escapes 
rapidly, and it has little effect except from the ether and alcohol. 1-5 c.c. 
(20-90 mins.). 

Nonofficial. 

Erythrol tetranitrate (CH 2 ON0 2 (CHON0 2 ) 2 CH 2 ON0 2 ) is a solid, and is 
recommended in doses of 0.05 G. (1 gr.), in pills, tablets or alcoholic solu- 
tion. Like nitroglycerin, it is a dangerous explosive, and one fatality has 
already occurred in forming it into pharmaceutical preparations. 

Therapeutic Uses. — The nitrites were introduced into therapeutics 
by Brunton, who advised their use in angina pectoris to relieve 
spasm of the arteries. They are certainly the most powerful depres- 
sants of the blood-pressure known, and may be used in all cases where 
this appears abnormally high. For rapid transient effects nitrite of 
amyl seems specially indicated, while nitroglycerin and nitrite of so- 
dium are more suited to produce a depression of some duration. Thus 
during the attack of angina pectoris, amyl nitrite is often found to give 



THE NITRITES. 475 

instant relief, but if nitrite of soda is administered every 4-6 hours, no 
attack may occur. This disadvantage of the metallic nitrites is the fre- 
quent eructation they produce, while nitroglycerin often causes severe 
headache, which, however, disappears in some cases after repeated use. 

Besides in angina pectoris, the nitrite series may be used in any con- 
dition in which it is supposed that the arterial tension may be lowered 
with benefit to the economy. Thus nitroglycerin has been advised 
in heart disease and has accordingly been placed by some among the 
heterogeneous group of " Cardiac tonics or stimulants." Its beneficial 
effects are not due to any direct action on the heart, but to its decreas- 
ing the resistance against which the systole is performed. In this way 
the contraction of the ventricle is rendered more complete, and the 
output of the heart may be increased. In weak hearts struggling 
against a high aortic resistance, this relief may be followed by marked 
benefit, and for this reason nitrite preparations (nitroglycerin) are often 
prescribed in chronic Bright' s disease. Digitalis causes a contraction of 
the peripheral arterioles along with its proper cardiac action, and the 
addition of nitrite may be advisable in some cases in order to neutralize 
this peripheral action. In those cases the nitrite of soda or nitrogly- 
cerin is of course preferable to amyl nitrite, whose action is too transient. 
(See Digitalis, page 460.) Amyl nitrite has been advised in cases of 
death from chloroform on the theory that it would benefit the circulation ; 
but as a matter of fact, it would appear strongly contra-indicated in 
those cases in which it is true that the heart is extremely depressed, 
but in which the arterial tension is practically zero. Its use is especially 
irrational, if, as has been suggested, the failure of the respiration is 
partly due to anaemia of the central nervous system. The cases in 
which recovery has occurred after this measure, may in fact be said to 
have recovered not owing to, but in spite of the use of amyl nitrite. 

In very advanced degeneration of the cardiac muscle fibre, the ad- 
ministration of amyl nitrite is distinctly contraindicated, for the blood- 
pressure is low and any further reduction may lead to syncope from 
anaemia of the brain, and to still greater weakness of the heart from 
the low pressure in the coronary arteries lessening its nutrition. 

Nitrite of amyl has been used largely in asthma and in cardiac 
dyspnoea. Its action is often beneficial and has been attributed to its 
depressing the bronchial muscles, which are supposed to be in a con- 
dition of spasmodic contraction in asthma. In the cardiac cases its 
action in removing the dyspnoea may be due to its lowering the pres- 
sure in the systemic arteries and thus relieving the heart. 

In some cases of headache, nitrite of amyl is of marked benefit, 
while in others it aggravates the condition. This is perfectly intel- 
ligible, as some forms of headache may be due to constriction of the 
arterioles while others are accompanied by a congested condition of 
the vessels of the head. 

From spasm of the circulatory organs, the use of nitrite of amyl 
has been extended to other forms of spasmodic seizures, such as epi- 
lepsy. It seems to be of little or no value, as indeed might be ex- 



470 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

pected from its pharmacological action. In some cases it even seems 
to increase the tendency to convulsions. 

Sweet spirits of nitre has long enjoyed a popular reputation as a 
diaphoretic and diuretic. It seems to have little action cither on the 
kidneys or the sweat glands, and might be discarded from the phar- 
macopoeia without loss. It is of more value as a carminative and 
flavor than for any other purpose. 

Bibliography. 

Brunton. Arbeiten aus der physiolog. Anstalt., zu Leipzig, iv., p. 101, and Journ. 
of Anat. and Phys., v., p. 92. 

Wood. Amer. Journ. of Med. Sciences, lxi., p. 422. 

Atkinson. Journ. of Anat. u. Phys., xxii., p. 225. 

Mayer u. Friedrich. Arch. f. exp. Path. u. Phann., v., p. 55. 

Hay. Practitioner, xxx., pp. 179-321. 

Leech. British Medical Journal, 1893, Vols, i., p. 1305 and ii., p. 4. 

Cash and Dunstan. Phil. Trans, of the Royal Soc, clxxxiv., B., p. 505. 

Gamgee. Ibid., clviii., p. 589. 

(iiacosa. Ztschr. f. physiolog. Chemie, iii., p. 54. 

Mitchell and Reichert. Amer. Journ. of the Medical Sciences, lxxx., p. 158. 

Haldane, MakgiU and Mavrogordato. Journal of Physiology, xxi., p. 160. 

Sckadew. Arch. f. exp. Path. u. Pharm., vi., 194. 

Filehne. Arch. f. Anat. u. Phys., 1879, p. 385. 

Marshall. Jour, of Phys., xxii., p. 1. 

Bradbury. Brit. Med. Journ., 1895, ii., p. 1213. 

C. Rosenthal. Archiv f. [Anat. u.] Phvs., 1888, p. 29. 

W. Rosenthal. Ibid., 1893. Supplement, p. 240. 

Laws. Journ. of Amer. Med. Ass., xxxi., p. 798. 

Winkler. Ztschr. f. klin. Med., xxxv., p. 213 ; xxxvi., pp. 30, 138. 

XXXII. ERGOT. 

Ergot is a parasitic fungus (Claviceps purpurea) which grows on the 
rye (Secale corn u turn or cereale) and occasionally on other kinds of 
grain, more rarely on other plants. It is of great importance in ther- 
apeutics and also in toxicology, as the use of bread and meal contain- 
ing it has frequently given rise to widespread epidemics. In these 
the chief symptoms consisted in gangrene of the limbs, or in convul- 
sive movements and contractures. 

The chemistry of ergot is still in an unsatisfactory condition, as its active 
principles seem to be peculiarly unstable, and are decomposed by compara- 
tively weak reagents. A large number of imperfectly isolated bodies have 
been described as occurring in it, but the first approach to a successful treat- 
ment of the subject was made by Kobert in 1884. He described three bodies 
as involved in the action of ergot, the first, Ergoiinic Acid, a nitrogenous 
acid of glucosidal nature, the second, Cornviine, an alkaloid, and the third, 
Sphacelinic Acid, sl resinous acid which contains no nitrogen. Various other 
bases have been observed in ergot besides cornutine, but most of them are 
entirely inert, and the others may owe their action to the presence of one or 
more of these three bodies, or may perhaps be identical with cornutine. It 
must be added that Kobert did not succeed in isolating completely any of 
these three poisons, but he was able to show that, while ergotinic acid be- 
haves in the same way as the members of the sapotoxin series, cornutine 
stimulates the central nervous system strongly and produces convulsions, 
while sphacelinic acid induces gangrenein animals. 

Jacobj has recently stated that the action of sphacelinic acid is due to a 



ERGOT. 477 

very poisonous resinous body, Sphacelotoxin, which seems to be capable of 
entering into loose combinations with various other constituents of ergot. 
He succeeded in isolating two such compounds, one of which, Chrysotoxiu 
proved to be a combination of sphacelotoxin with the weakly acid, inactive 
body, Ergoclirysin, the other of which Secalintoxin, was a similar compound 
of sphacelotoxin and an alkaloid, Secaline. Sphacelotoxin he found to be a 
very unstable compound, which kept better when in the form of chrysotoxin. 

The action of ergot as known at present is therefore a complex 
which may be analyzed into three factors : 1. That due to one or more 
bodies somewhat resembling sapotoxin in action and contained in an 
impure form in the ergotinic acid of Kobert. 2. That due to one or 
more convulsive poisons contained in the cornutine of Kobert, and 3, 
that due to a gangrene-producing poison, which is contained in the spha- 
celinic acid of Kobert, and has been termed sphacelotoxin by Jacobj. 

While Cornutine is not a pure principle and its effects may be due 
to the interaction of several poisons, the train of symptoms is per- 
fectly distinct from those induced by the other constituents of ergot, 
and the name may be used to indicate the cause of these, without any 
definite understanding as to the nature of the body. In frogs it 
induces changes in the skeletal muscles similar to those described 
under veratrine, but, unlike the latter, does not affect the heart. In 
both frogs and mammals convulsions are observed and seem to be due 
to stimulation of the medulla oblongata and the basal ganglia, for they 
disappear in the frog when the medulla oblongata is destroyed, and 
are mainly clonic in nature. In the dog the symptoms consist of rest- 
lessness, salivation, vomiting, and purging. The pulse is slow and 
irregular, and after somewhat larger doses clonic convulsions set in 
with intervals of depression. The respiration ceases during one of 
these, while the heart continues to beat for some time. 

The alteration in the contraction of the muscles is due to direct 
action on the muscular fibre, similar to that of veratrine, while the other 
symptoms, like those from picro toxin, are caused by stimulation of the 
medulla oblongata and the nervous centres in its neighborhood. The 
slow rhythm of the heart can be removed by section of the vagi, and 
is therefore due to the inhibitory centre. The vaso-constrictor centre 
is also stimulated, and a considerable increase in the arterial pressure 
is thus caused, although this may be concealed by the slowness of the 
heart. Neither heart nor vessels are affected directly. The nausea, 
salivation and vomiting seem to be the result of medullary action also. 
Kobert observed that both stomach and bowel contracted powerfully 
under cornutine, and that wave-like movements occurred at the same 
time in the uterus, whether pregnant or not. These movements w r ere 
not continuous, but resembled peristaltic contractions and did not tend 
to empty the uterus. They were not produced in the excised organ 
when it was perfused with blood containing cornutine, and he there- 
fore supposed that they were the result of some action on the central 
nervous system. After large doses of cornutine the stimulation of the 
central nervous system passes into paralysis and the respiration ceases. 



478 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

Sphacelotoxin differs from all other known poisons in producing 
gangrene of various organs, more especially in fowls and pigs. 

In the frog the symptoms consist of depression and paralysis of 
the central nervous system. In most mammals (dogs, cats, rabbits, 
and guinea-pigs) the chief symptoms arise from irritation of the ali- 
mentary canal — salivation, vomiting and some purging — which is 
induced whether the drug be administered by the mouth or subcuta- 
neously. Later some signs of excitement may be observed, followed 
by depression and weakness, the excitement apparently being due to 
cerebral action. Kobert found numerous extravasations of blood in the 
stomach, intestine, and other organs, especially when the drug was 
given for some time and chronic poisoning induced. No gangrene 
could be elicited in these animals. 

In fowls a much more characteristic train of symptoms is found to 
follow the administration of sphacelotoxin. A cock soon appears 
drowsy and somewhat dyspnoeic, and the comb loses its bright scarlet 
color and becomes blue and cyanotic, especially at the tips. Purging 
and sometimes vomiting follow, and the animal has often great diffi- 
culty in preserving its balance, swaying to and fro very much as does 
a patient suffering from locomotor ataxia. After small doses the 
symptoms may pass off, but when larger quantities have been injected, 
and especially if chronic poisoning is induced, the comb becomes dry 
and hard and eventually falls off without any haemorrhage. The 
wattles, tip of the tongue, wings and spurs may undergo the same 
process. It refuses food, loses flesh and becomes weak and somnolent, 
but may recover if the treatment be stopped ; otherwise it dies of 
inanition and general weakness. The vessels of the comb are found 
to be filled with a transparent " hyaline " mass with a narrow streak 
of red corpuscles here and there, and it is evident that a typical dry 
gangrene has been induced. Marked irritation of the mucous mem- 
brane of the crop, stomach and bowel is present, with numerous ex- 
travasations, frequently with circumscribed areas of necrosis. CEdema 
and ecchymoses are often met with in the subcutaneous tissue and also 
in the internal organs, and a curious substance resembling amyloid 
was seen in the liver by Gninfeld. No alteration of the central ner- 
vous system has been detected after careful examination. In pigs, the 
ears become dark-colored and cyanotic and the tips undergo dry 
gangrene and fall off. Gangrene is also observed in the extremities 
and in different parts of the skin of the trunk, and haemorrhages into 
internal organs occur, especially in the bowel. 

The gangrene appears to be due to a prolonged contraction of the 
arterioles shutting off the blood supply of the parts and leading to a 
hyaline formation in the lumen and walls of the arterioles, which 
effectually obstructs the circulation after the muscular coats have 
relaxed. The constriction of the arterioles has been shown to occur in 
animals in which no gangrene follows, but is probably not so extreme 
in these. This constriction of the arterioles of course induces an 
increase in the blood-pressure, which was found by Kobert to be of 



ERGOT. 479 

considerable extent, while Jacobj found it less marked. Curiously 
enough, the blood-pressure in the fowl has not been examined under 
sphacelotoxin, although it might be expected to be more augmented in 
these than in many other animals. 

Kobert supposed that the arterioles were constricted by the increased 
activity of the vaso-motor centre, but Jacobj has shown that there is 
also some peripheral action, for the blood-pressure rises after division 
of the spinal cord, and the flow of blood through an excised organ is 
considerably retarded when sphacelotoxin is added to it. He there- 
fore considers that the muscular wall of the vessel is acted on directly, 
as well as through the central nervous system. 

Jacobj found that sphacelotoxin often induced abortion in pregnant 
animals, and concludes that it provokes uterine contractions, which 
are not tetanic in nature, but which rather resemble the normal peri- 
staltic contractions of the uterus during labor. These wave-like con- 
tractions move the foetus towards the os uteri, and eventually cause its 
expulsion. He found that abortion could be induced without serious 
injury to either parent or young. The contractions of the uterus may 
be due to some action on the spinal cord, as has been generally believed, 
but it must not be forgotten that the uterus is capable of automatic 
movement and that the young can be expelled from it after destruc- 
tion of the spinal cord, so that it seems not unlikely that ergot acts 
rather on the uterine fibres directly than through the nervous centres. 
This uterine action is elicited in animals in which ergot does not induce 
gangrene, such as the rabbit and cat. 

The Ergotinic Acid of Kobert seems to have little or no effect when given 
by the mouth, but induces depression and paralysis of the spinal cord when 
injected subcutaneously or intravenously in frogs and mammals. The higher 
divisions of the nervous system seem less readily affected, although the 
brain is also depressed, and unconsciousness and collapse may follow. The 
blood-pressure is much reduced from depression of the vaso-motor centre, 
while the heart seems comparatively little affected. Death occurs from 
paralysis of the respiratory centre. 

In addition to these three bodies there are probably other active principles 
contained in ergot, for some preparations of the drug cause very distinct 
slowness and weakness of the pulse., which does not seem to be induced by 
any of the three constituents described above. None of the three principles 
have been used in medicine in a sufficiently pure form to allow of a descrip- 
tion of their effects. A so-called " cornutine " has been employed to a lim- 
ited exent, but it contained considerable quantities of sphacelotoxin. 

Ergot has rarely given rise to Acute Poisoning in Man, but in several 
cases in which it was taken in order to induce abortion, the symptoms 
consisted in collapse, with a weak, rapid pulse, tingling, itching and 
coldness of the skin, unquenchable thirst, vomiting and diarrhoea, 
confusion or unconsciousness, haemorrhages from the uterus, abortion, 
and some icterus. Ecchymoses were found in the subcutaneous tissue 
and in many internal organs. Somewhat similar symptoms have been 
produced in animals. 

Chronic Poisoning was formerly not uncommon, and in fact frequently 
gave rise to widespread epidemics, from the use of bread containing ergot 



480 ORGANIC DRUGS ACTING AFTER ABSORPTION, 

after poor harvests and especially in wet seasons. Of late years these 
epidemics have become rare except in Russia, but some of the " plagues M 
of mediaeval Europe may have been due to ergot poisoning. 

The symptoms of ergotism are sharply divided into two groups, 
those of gangrene and those of nervous disorders. In some epidemics 
both the gangrenous and the convulsive forms are present, but, as a 
general rule, one is much more prevalent than the other, at one time 
gangrene being almost invariably present, while in another epidemic, 
the convulsive type is the more common. The gangrene is generally 
developed in the limbs, especially in the fingers and toes ; sometimes 
the whole arm or leg becomes cold and anaesthetic, dark in color, and 
then dry, hard and shrunken, and falls off with little or no pain and 
no haemorrhage. Symptoms of such severity are rare, however, and 
in milder cases only the skin necroses. Gangrene of internal organs 
also occurs, resulting in cataract in the lens of the eye, or ulcers in the 
bowel and stomach, and sometimes affecting a whole organ such as a 
lung or the uterus. Abortion is seldom mentioned in the accounts of 
chronic ergot poisoning, and pregnancy seems in many cases to have 
run its ordinary course. Gangrenous ergotism is evidently due to 
sphacelotoxin causing prolonged contraction of the vessels, followed 
by hyaline thrombosis. The blood vessels in man therefore seem to 
be acted on in the same way as those of the fowl and pig, while those 
of the other mammals escape. 

In spasmodic ergotism the first symptoms are depression, weakness 
and drowsiness, often with headache and giddiness, painful cramps in 
the limbs, and itching and formication of the skin. In severe cases 
paroxysmal convulsions set in, generally clonic, and often epileptiform, 
but leaving as sequela? contractures in the limbs, or less often in the 
trunk muscles. Some intellectual weakness often follows recovery 
from ergot poisoning, this not infrequently amounting to complete 
dementia, but the disease was immediately fatal in a large proportion 
of cases in earlier times. Cornutine was supposed by Kobert to be the 
cause of the convulsive form of ergot poisoning, and his explanation 
has been generally accepted, although it is not without difficulties, 
for chronic poisoning with cornutine does not produce any symptoms 
whatever in animals, unless doses sufficient to cause acute poisoning are 
given. On the other hand, fowls poisoned with sphacelotoxin suffer 
from ataxia and other nervous symptoms, so that it is probable that 
other factors besides cornutine are involved in the production of these 
symptoms in epidemic poisoning and the entire action may perhaps be 
due to sphacelotoxin. 

The accounts of different observers of the action of ergot on the individual 
organs present great discrepancies. This is explained by the difference be- 
tween the preparations used and by the extreme instability of the more active 
principles. The effects on the circulation are especially liable to vary, for in 
many cases the heart is rendered slow and weak, sometimes apparently from 
cornutine acting on the vagus centre, at other times from some unknown 
body affecting the muscle directly ; in others acceleration of the heart has 
been observed. Very often the preparations known as ergotin are stated to 



ERGOT. 481 

cause a very marked fall in blood-pressure, while others which probably 
contain larger amounts of sphacelotoxin and cornutine contract the arterioles 
and increase the blood-pressure. Further dispute has arisen as to whether 
this effect is central or peripheral. It is obviously unprofitable to discuss 
these questions, however, as scarcely any two of the investigators have used 
the same preparation, and there is no means of judging of what constituents 
their drugs were composed. 

The effects of ergot and its preparations on the Uterus are no less a 
matter of dispute. Many gynaecologists consider that it does not excite 
movements in the uterus, but that when labor has commenced, it pro- 
longs the contractions and may, in fact, cause a continuous contrac- 
tion (tetanus) of the muscular fibres, which delays the expulsion of 
the contents and imperils the life of both mother and child. On the 
other hand, some believe that ergot induces uterine contractions and 
strengthens those present in labor, without necessarily hindering the 
periodic relaxation of the muscle, and Jacobj's results with sphacelo- 
toxin would confirm the latter view. These discrepancies are undoubt- 
edly to be explained by the fact that preparations of ergot are very often 
employed which are entirely inert, while in other cases effects have been 
credited to ergot which have appeared before it w~as possible that the 
drug was absorbed. The action of ergot on the uterus is not sufficiently 
certain to permit of definite statements, but it seems unquestionable 
that in animals it produces abortion, and must therefore induce move- 
ments similar to those occurring in normal labor. It is probable that 
in the human uterus the same effect is induced, while the so-called 
" tetanus uteri " may perhaps be explained by the use of large doses or 
very .active preparations. It may very well happen that a substance 
which in small quantities only increases the irritability of the muscle 
or strengthens the normal contractions, may induce very prolonged 
contractions when applied in larger quantities (compare the action of 
digitalis on the frog's heart). 

Some experiments have been performed to find whether the contrac- 
tions of the uterus under ergot are due to action on the uterus itself or 
on the nervous centres. But the results are again contradictory and 
need not be detailed. 

Kobert at first supposed that sphacelotoxin was the more important 
body in the action of ergot on the uterus, and this view has been held 
by most authors since then, and has been supported in particular by 
Jacobj. Of late years, however, Kobert has come to regard cornutine as 
the chief factor in this result, although there seems no satisfactory work, 
either experimental or clinical, in support of his more recent view. 

The vomiting and diarrhoea which are sometimes observed after 
ergot may be of central origin, but are generally supposed to be due to 
direct action on the muscular coats of the stomach and intestines sim- 
ilar to that described by some authors as occurring in the uterus. 

Preparations. 

U. S. P. — Ergota, ergot of rye, the sclerotium of Claviceps purpurea re- 
placing the grain of rye. When more than one year old it is unfit for use. 
31 



482 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

Extractum Ergotse, 0.2-1 G. (3-15 grs.). 

EXTRACTUM ERGOTSE FLUIDUM, 4-8 C.C. (1-2 11. (ll'S). 

Vinum Ergotse, 10-20 c.c. (5-10 11. drs.). 

B. P. — Ergota, the sclerotium of Claviceps purpurea, originating in the 
ovary of Secale cereale. 20-60 grs. 

Extractum Ergotse (Ergotin), 2-8 grs. 

Extractum Ergotje Liquidum, 10-30 mins. 

Tinctura Ergotse Ammoniata, \-l fl. dr. 

Infusum Ergotse, 1-2 11. oz. 

Injectio Ergotse Hypodermica, 3-10 mins. (subcutaneously). The in- 
jection ougljt to be recently prepared. It is about 33 per cent. 

The fluid or liquid extracts and the hypodermic injection are the best of 
the preparations. The vinum is very often quite inert, and the extract being 
prepared from the fluid extract by heat is liable to contain less of the un- 
stable active constituents than the latter. A very large number of prepa- 
rations, such as ergotin, ergotinic acid, sclerotinic acid, cornutine, etc. , are 
simply more or less purilied extracts and have no advantage over the phar- 
macopceial preparations ; in fact the chemical manipulations through which 
they are obtained are often such as are likely to remove, or render inert, the 
active bodies of the crude drug. 

The dose of the preparations of ergot is exceedingly variable, as a quantity 
sufficient to induce very marked effect in autumn, may be found entirely 
inert in the following spring. Grunfeld, in fact, states that in March and April 
twelve times as much is required as in July and August, and that in May 
and June the drug is entirely without effect in any dose, but this is probably 
an exaggeration, unless where the ergot has been carelessly stored. Accord- 
ing to Jacobj, the pure chrysotoxin may be kept for years without deterior- 
ating. Sterilized fluid extract is said to keep better than the ordinary 
preparations, but the whole subject requires further research. 

Therapeutic Uses. — Ergot is used very largely in obstetrics to pro- 
mote the contraction of the uterus, but considerable divergence is met 
with in the views of different authorities as to the special indications 
for its exhibition. Thus, those who believe that ergot increases the 
irritability of the uterus and produces rhythmical contraction without 
tetanus, advise that it be given whenever the pains seem insufficient, 
and more especially when this occurs in the later stages of labor. 
Others are possessed with perhaps an exaggerated apprehension of the 
prolonged uterine contractions, which they consider delay labor and 
tend to cause asphyxia in the child, and therefore advise that ergot be 
used only to preserve the uterus in a contracted condition after the 
child and placenta have been expelled. In every case the attendant 
should of course satisfy himself before giving ergot of the absence of 
all actual impediments to the passage of the child, such as contracted 
pelvis, abnormal presentation, or great rigidity of the soft parts, and 
when it is administered before the head emerges, the dose ought to be 
small, as otherwise the tonic contraction may be induced. When the 
head is about to emerge, on the other hand, a large dose may be given 
to promote the permanent contraction of the uterus and thus to pre- 
vent post-partum haemorrhage. When the latter has once set in, er- 
got is of less immediate service, as it is slowly absorbed, and no ef- 
fects follow for some twenty minutes or more. Whenever there is any 
reason to fear that weakness of the uterine contraction and haemor- 
rhage may set in after the expulsion of the child, ergot ought to be 



ERGOT. 483 

given when the head emerges, and many gynecologists recommend this 
as a routine treatment. 

Ergot hinders post-partum haemorrhage, chiefly by promoting the 
contraction of the uterus. In other forms of haemorrhage — from the 
stomach, intestines, kidneys, lung or uterus — in which the bleeding 
point cannot be reached, it is often advocated in the belief that it con- 
tracts the walls of the vessels and thus arrests the flow of blood. 
These haemorrhages so often cease spontaneously that it is difficult to 
estimate the value of any remedy, but it may be questioned whether 
ergot merits its reputation in these cases. Its action in healthy ani- 
mals certainly indicates that the contraction of the vessels is confined 
to certain organs, otherwise there would be a more distinct increase in 
the blood-pressure. And there is no reason to suppose that a more 
intense action is exerted on a ruptured vessel than on the uninjured 
ones of other organs ; but unless this is the case the use of ergot may 
be rather harmful than remedial, for any increase in the general blood- 
pressure, such as would follow the contraction of the vessels through- 
out the body, must increase the escape of blood from the injured ves- 
sel. In these cases, as in labor, the fluid extract is often given by the 
mouth, but this extract or the special preparation of the B. P. is 
sometimes injected with the hypodermic needle. It is irritant, and 
ouo-ht therefore to be injected deeply into the muscle, rather than into 
the subcutaneous tissues. 

The effect of ergot in inducing contraction of the uterus has been 
used in the treatment of subinvolution and of myomata of that organ ; 
the involution of the uterus certainly seems to be favored by it, 
but the results in tumor are more open to question. In any case the 
prolonged treatment of this, or of any other condition with ergot 
is to be deprecated, for if the drug is active at all, it may induce gan- 
grene or spasmodic ergotism. The same criticism might be applied 
to the ergot treatment of a number of other diseases, such as aneurism, 
diabetes, or pneumonia ; and in addition, it does not seem to have any 
greater effect in these than many other less dangerous remedies, which 
have been equally vaunted as specifics, and have been found equally 
valueless. 

Bibliography. 

Robert. Arch. f. exp. Path. u. Pharm., xviii., p. 316. 

Griinfeld. Arb. a. d. pharmakol. Institute zu Dorpat, vii., p. 108 ; xii., p. 295. 
Jacobj. Arch. f. exp. Path. u. Pharm., xxxix., p. 85. 
Houghton. Therap. Gazette, 1898, p. 433. 
Walker. Arch. f. Psychiatrie, xxv., p. 383. 
Jahrmarker. Ibid., xxxv., p. 109. 

The earlier literature is to be found in Griinfeld' s paper, hut the student is recom- 
mended to read the above papers before proceeding to the earlier work. 

Ustilago Maydis (U. S. P.), or corn smut, a fungus growing on maize, is 
entirely different from ergot, and, according to Robert, is quite inert. It 
has been used as a substitute for ergot, on the supposition that it would re- 
semble it in action as well as in origin, but has proved quite ineffective. 

Cotton-root Bark (Gossypii Radicis Cortex, U. S. P.) has been used by the 
Southern negroes to produce abortion, and is said by some gynecologists to 



484 ORGANIC DRUGS ACTING AFTER ABSORPTION. 

resemble ergot in action on the uterus. It has little or no effect on animals, 
except in enormous doses, and is generally stated by those who have tested 
it to be entirely devoid of action in man. The fluid extract is the only 
preparation in the pharmacopoeia. 



PART III. 

COMBINATIONS OF THE ALKALIES, ALKALINE 
EARTHS, ACIDS AND ALLIED BODIES. 

SALT-ACTION. 

The action of most of the substances discussed in the foregoing pages 
may be best explained by supposing that they cause some change in 
the living matter of one or more organs through a specific chemical 
affinity for it. Thus strychnine may be supposed to act on the spinal 
cord by forming a chemical compound with the protoplasm of the 
nerve cells, while prussic acid changes protoplasm generally, through 
a similar affinity for it. 

Some bodies, on the other hand, seem to have little specific affinity 
for living matter, but affect it largely as they do dead colloid sub- 
stances, through changing the physical properties of the fluids contained 
in it or surrounding it. This action is seen best in the effects of some 
of the salts of the alkalies, and is therefore known as " salt-action," 
although it is not confined to these, but is shared by any soluble, 
diffusible body which can circulate in the tissues in sufficient quantity. 
The salts of strychnine or of prussic acid are undoubtedly capable of 
inducing physical changes similar to those observed after chloride of 
sodium, but they play no part in the symptoms induced by these 
poisons, because animals die from their specific action long before the 
quantity necessary to induce the " salt-action " can be absorbed. In 
the case of less poisonous organic substances, such as sugar and urea, 
however, many of the features of salt-action may be observed. 

Much light has been thrown on the nature of salt-action by the re- 
cent advances in physical chemistry, which have shown that many of 
the changes in the animal body are analogous to those observed in the 
chemical laboratory. When an aqueous solution of sugar or salt is 
carefully poured on distilled water, so that two layers are formed, a 
process of Diffusion commences, the dissolved molecules passing through- 
out the fluid until the whole becomes homogeneous, each cubic centi- 
metre containing an equal number of molecules of sugar or salt. If 
instead of distilled water, a solution of another salt be used, the same 
process results, the two bodies diffusing throughout both fluids until 
these become homogeneous ; and if the fluids be separated by a mem- 
brane which offers no obstacle to the penetration of the water and 
salts, a similar interchange occurs. When a membrane is used which 
does not allow the salt to pass through it, a different result is observed ; 

485 



486 INORGANIC SALTS, ACIDS AND 11 ASKS. 

if it separates salt solution from pure water, the latter passes through 
until it is exhausted, or until some factor such as hydrostatic pressure 
puts a limit to further movement. This is readily intelligible, for the 
pure water can pass without hindrance towards the salt, but having 
rendered the solution more dilute, it cannot diffuse in the opposite 
direction, because this would be equivalent to forming a more concen- 
trated solution of the salt, and this requires the expenditure of energy, 
such as heat, while in the case in point there is no energy available for 
this purpose. A similar result is obtained if the membrane separate 
solutions of a non-permeating and of a permeating salt, the latter 
passing through with the fluid in which it is dissolved until some ex- 
traneous factor counterbalances the diffusion. 

The resistance offered by a non-permeating salt to the passage 
through the membrane of the fluid in which it is dissolved is known 
as its Osmotic Pressure and varies with the number of molecules and 
ions (see page 488). When both the salts in solution on the opposite 
sides of the membrane are unable to penetrate through it, the move- 
ment of the fluid is determined by the relative osmotic pressure on the 
two sides, water tending to pass from the solution with the lower 
osmotic pressure (the hypotonic solution) to that with the higher (hyper- 
tonic) until an equilibrium is established by the osmotic pressure be- 
coming equal on the two sides, when the solutions are said to be isotonic. 
As a general rule, however, membranes are partially permeable to both 
salts, and the movement of the fluid is determined by the' relative 
osmotic pressure of the fluids divided by the rate at which the salts 
pass through the membrane. If sufficient time is allowed to elapse, 
the two solutions will become identical in composition, but during a 
short period, the details of the process are difficult to follow, and the 
complexity is infinitely greater when instead of a single salt on each 
side of the membrane there are several salts each differing in its per- 
meability and concentration. The direction of the flow is then deter- 
mined by the sum of the osmotic pressure on each side divided by the 
penetrating power of each individual substance. 

In the animal body such membranes as are used in physical experi- 
ments are not met with, but the cells consist of colloid substances con- 
taining fluid and diffusible bodies, and are surrounded by liquids which 
are practically salt solutions isotonic with the contents of the cells ; 
any change in the contents of the cell or in the lymph surrounding it 
must of necessity give rise to a certain movement of the fluids in the 
same way as if each cell were surrounded by a membrane. All the 
cells of the body are permeable by water, and a dilution of the fluids 
surrounding them is therefore followed by an increase in their fluid 
contents and swelling. On the other hand, some salts seem to diffuse 
into cells practically without resistance, while others fail altogether to 
do so, or penetrate only very slowly. The subject has been investi- 
gated with most care in the red blood cells, which are found to be pene- 
trated by ammonium chloride and some other salts, while they are 
impermeable by sodium chloride and the other salts of the fixed 



SALT-ACTION. 487 

alkalies. Accordingly, when the red blood cells are surrounded by a 
solution of ammonium chloride, whatever its concentration, their fluid 
contents are increased ; they swell up and eventually lose their hserno- 
globin, exactly as if they had been placed in pure water. When 
they are placed in an isotonic solution of chloride of sodium, 1 they 
remain unchanged in size, while in a hypertonic solution their fluid dif- 
fuses out, and they shrink ; a hypotonic solution acts like pure water, 
the osmotic pressure of the salts in the corpuscles overcoming the 
smaller osmotic pressure of the surrounding fluid. The behavior of 
a cell towards salts therefore varies with each individual salt. Solu- 
tions of those by which it is perfectly permeable have the same ef- 
fects as pure water ; but the less diffusible the salt, the more tendency 
it has to prevent the entrance of the water in which it is dissolved, and 
if in sufficient concentration, to withdraw fluid from the cell. A per- 
fectly diffusible substance can never prevent the entrance of fluid, 
however concentrated be its solution. 

All the cells of the body do not resemble each other in their per- 
meability, nor in the salts which diffuse into them. For example, the 
intestinal epithelium takes up some of the salts of the alkalies, while 
the red blood cells do not. 

An even more obscure relation between the salts and colloids has 
been discovered by Hofmeister, who found that gelatin plates thrown 
into weak salt solutions absorb more fluid than when they are put in 
distilled water, and who inferred from this that colloid substances 
have a special affinity for salts quite apart from their permeability by 
water, and that they are not merely passively permeated by salt solu- 
tions, but have an active attraction for some of the salts contained in 
them. This affinity, which may depend on the same factor as the 
permeability of the cell, varies for different salts. 

The role played by the physical forces in the salt-action is thus determined 
not only by the physical properties of the fluids, but also by the "affinity " 
of the cell contents for certain of the constituents of these fluids. In con- 
clusion it may be stated that one school of physiologists holds that these 
physical forces suffice to explain not only the salt-action, but the whole 
processes of absorption and excretion, while another school teaches that the 
physical forces merely influence the processes of nutrition, which depend 
oh forces hitherto unexplained and possibly exercised only by the living- 
protoplasm. 

The penetrating power of salts seems to be connected with the property 
which many of the n possess of precipitating certain colloid substances from 
their solutions in water, for those salts which permeate gelatin plates are 
found to precipitate colloids less than others. Thus the sulphates of the alka- 
lies, which permeate gelatin plates with difficulty, throw globulins out of 
Solution much more readily than the chlorides. Here again, however, 
different colloids vary in their affinities, some reacting to one sulphate and 
not to another. This reaction is not confined to the proteids but extends to 
many carbohydrate colloid substances. 

In the dilute solutions found in the tissues, the salts do not exist as 

1 An isotonic solution is here used to indicate a solution in which the osmotic pressure 
is equal to that of the blood serum, and (presumably) to that of the contents of the red 
blood cells. 



488 INORGANIC SALTS, ACIDS AND BASES. 

such, but are largely dissociated into two or more Ions charged with 
positive and negative electricity. Thus if a small quantity ofpotassic 
chloride be dissolved in water, it is dissociated into a positive K ion 
(Kation) and a negative CI ion (Anion). 1 Similarly sodium sulphate 
dissolved in water exists as two Na ions and a negative S0 4 ion. One 
effect of this is that the osmotic pressure of such a dilute solution 
diverges considerably from what might be expected if it were calcu- 
lated from the number of molecules present, because each of the ions 
exerts the same osmotic pressure as a whole molecule. But a more im- 
portant fact is that the ions of a salt, and not the whole molecule, form 
chemical combinations, and thus exert their pharmacological action. 
Thus what is known as the action of many poisons is really the action 
not of the molecule as a whole, but of one of the ions. For example, 
cyanide of potassium is said to possess a very poisonous action, but 
this is due not to the molecule KCN as such, but to the CN ion, 
which forms from it in solution. When ferroeyanide of potassium is 
dissolved, on the other hand, no CN ion is formed, the salt dissociat- 
ing into the K and Fe (CN) 6 ions, and ferroeyanide of potash is there- 
fore entirely devoid of the cyanide action. In the same way the 
corrosive effects of potassium or sodium hydrate are not due to the 
potassium or sodium, but to the hydroxyl ions (HO), for the same K 
or Na ions are obtained when KC1 or NaCl is dissolved, but neither 
of these is corrosive. Thus when a dissociable body is administered, 
not one, but two, separate agents are put in action in the tissues, and 
in describing the effects of one of these dissociable bodies, the effects 
of each ion have to be taken into consideration. In the organic 
materia medica, many such substances occur, but in the great majority 
of them the action of one ion is so much more powerful than that of 
the other that the less important one may be neglected. Thus, mor- 
phine sulphate in the body exists as a morphine and a sulphate ion, 
but the action of morphine is so much the more powerful that the sul- 
phate ion may be left out of account. This is shown by the fact that 
morphine hydrochlorate, which is dissociated into morphine and chlo- 
ride ions, has practically the same action as morphine sulphate. In 
the same way the positive ion (Na, K, etc.) of the cyanides may be 
neglected, because the negative CN ion is so poisonous that the posi- 
tive ion can never be present in the tissues in sufficient quantity to 
elicit any action. 

When, however, less poisonous substances are involved, the case is 
quite different. Thus, although the hydrobromate and the sulphate 
of morphine may be described as possessing the same action, because 
the morphine ion alone is taken into account, the sulphate and brom- 
ide of potassium induce quite different symptoms, 2 because here larger 

1 These ions are not to be confused with atoms of potassium and chlorine for they 
possess none of the chemical properties of these elements ; the physical difference con- 
sists in each ion being charged with a burden of electricity, positive or negative. 

2 Even at the present day it is sometimes a matter of discussion whether the bases or 
the acids are the determining factors in the action of the salts of the alkalies. The 
question depends entirely upon which salts are compared. If chloride of sodium and 



SALT-ACTIOX. 489 

quantities can be administered, and the S0 4 and Br ions are present 
in sufficient quantities to elicit their specific action, which is quite as 
important as that of the K ion. 

In this connection it is to be noted that many bodies are not disso- 
ciated. For example, potash, KHO, and alcohol, C 2 H.HO, both con- 
tain HO, but in the former the hydroxyl is dissociated in water, 
while the latter remains undissociated. Thus, when KHO comes in 
contact with a mucous membrane, the molecule does not act as such, 
but the effects are due to the HO ion, and to a less extent, to the K 
ion. On the other hand, alcohol acts as a molecule, and the caustic 
effects of the HO ion are not observed under it. A similar contrast is 
offered by the effects of the dissociable KBr and bromated camphor, 
which is not dissociable but acts as an entire molecule. It is therefore 
vain to expect the bromide action from this compound, for the bromides 
act from the presence of the bromide ion, which is not formed from 
monobromated camphor. 

This renders the classification of the inorganic salts a matter of 
some difficulty, for it is necessary to consider the action of each ion 
alone, and then to find how far its effects are modified by the presence 
of the other ion with which it is associated in the molecule. It is 
obviously illogical to consider under a " potassium series " all the 
salts of potash, for in many of these the K ion is of no importance, 
while in others it is the chief factor. 

The effects of an ion cannot be determined except by administering 
it along with another in the form of a salt, but certain ions are so inac- 
tive in the tissues that if any effect is noted after a compound of 
which they form part, the action can be ascribed with certainty to the 
other ion, unless the change arises from alteration of the physical prop- 
erties of the fluids. For example, the sodium ion (Na) and the chloride 
ion (CI) are both practically inert, except in so far as they change the 
osmotic pressure. Thus, if a sodium salt or a chloride be found to 
cause some change which is not due to the physical alteration, the ac- 
tion is attributed to the other ion of the molecule. Before entering 
on the study of the action on the ions, however, it is obviously neces- 
sary to learn the symptoms caused by alteration of the physical prop- 
erties of the fluids, and this can best be done by examining the effects 
of bodies which act only in this way, namely, chloride of sodium and 
water. 

Bibliography. 

Xaegeli. Pflanzenphysiologische Untersuchungen, 1855. 

De Vries. Pringsheim's Jahrb. f. wissenschaft. Botanik, xiv., p. 427. 

Hamburger. Arch. f. Anat. u. Phys., 1887, p. 31 ; 1899, Suppl., p. 431. 

Eykmann. Pfliiger's Arch., lxviii., p. 58. 

Hedin. Ibid.,lxx., p. 525. 

Koeppe. Ibid., lxvii., p. 189. 

Gryns. Ibid., lxiii., p. 86. 

chloride of potash be compared, the determining factor is the base, but if a chloride 
and a cyanide be in question, the base with which they are combined is practically of 
no importance. 



490 INORGANIC SALTS, ACIDS AND BASES. 

Hofmeister. Arch. f. exp. Path. u. Pharm., xxiv., p. 247; xxv., p. 1 ; xxvii., p. 
395; xxviii., p. 210. # 

Lewith. Ibid., xxiv., p. 1. 

Pohl. Zts. f. physiol. Chem., xiv., p. 151. 

Hamburger. Virchow's Arch., cxl., p. 503. Zts. f. Biologie, xxx., p. 143. 

For the adaptation of the theory of ions to pharmacology, consult : 

Scheurlen. Arch. f. exp. Path. u. Pharm., xxxvii., p. 74. 

Scheurlen u. Spiro. Munch, med. Woch., 1897, p. 81. 

Loeb. Pfliiger's Arch., lxix., p. 1. 

Schrniedeberg. Grundriss der Arzneimittellehre, 3d ed., pp. 241-243. 

Kronig u. Paul. Zts. f. Hyg., xxv., p. 1. 

I. SODIUM CHLORIDE AND WATER. 

The most typical example of salt-action is presented by chloride of 
sodium, for this salt is always present in large quantities in the body, 
and has practically no specific action ; the sodium and chloride ions 
are ordinary and necessary constituents of the fluids of the body. The 
action of this salt is therefore limited to the alteration in the physical 
properties of the fluids, which its presence in excess or in limited 
amount induces. In the same way the action of water is due only to 
its diluting the body fluids and lessening their osmotic pressure, and 
it may therefore be described along with that of salt. 

Most of the tissues hitherto examined in regard to this point have 
proved permeable by both the Na and the CI ions, but in every case 
there is a certain amount of resistance offered so that the presence of 
salt in the fluid round a cell always prevents its free diffusion into the 
interior ; i. e., sodium chloride solution exerts osmotic pressure on the 
cell. The molecular weight of common salt being small, the osmotic 
changes induced by it are greater than those induced by an equal 
weight of most other salts, because a larger number of molecules ex- 
ist in each gramme. It also dissociates into its two ions more readily 
than many others, and this lends it still greater osmotic power. 

A common example of the osmotic action of salt is seen in its use 
to preserve meats from putrefaction, which it accomplishes by with- 
drawing the fluids of the meat, and thus rendering it dry and hard 
and unsuitable for the growth of microbes. 

In the same way the Red Blood Corpuscles shrink in size when they 
are placed in a solution of salt which is stronger than the blood-plasma 
(hypertonic), because the water is withdrawn from them. In dilute 
(hypotonic) solution, on the other hand, or in water, they swell up be- 
cause they absorb water, while in solutions of the same osmotic pres- 
sure as the plasma (isotonic) they remain unaltered in size. When 
water is absorbed into the corpuscles some obscure change takes place 
in them, and the haemoglobin diffuses into the surrounding liquid. 

Muscle is affected in a similar way, strong salt solutions withdrawing 
fluid from it, while weaker ones are absorbed, and both tend to destroy 
its vitality in a longer or shorter time. In isotonic salt solution, on 
the other hand, muscle preserves its irritability for many hours. 
Strong salt solutions irritate exposed Nerves from the withdrawal of 
their fluid contents, and on the other hand, distilled water is equally 
fatal to them. 



SODIUM CHLORIDE AND WATER. 491 

These changes are undoubtedly due to the imperfect permeability of the 
cells by the sodium and chloride ions, and as regards the red blood cor- 
puscles, it is definitely known that salt penetrates them with the greatest 
difficulty if at all, and the changes induced in them by solutions of different 
concentration and by water are due to the alteration of their fluid contents 
only. If this were true for all cells, the isotonic solution would preserve 
them in a normal condition until they slowly perished for want of oxygen 
an 1 from exhaustion of their reserve of food. But this is found not to be 
the case, for muscle suspended in isotonic solution often develops a more or 
less rhythmical series of contractions, while the frog's heart ceases to beat 
after a time when it is perfused with isotonic salt solution, although it has 
not exhausted its energy entirely. Similarly some ova aud fish living in sea 
water die if they are put in a solution of sodium chloride isotonic with sea 
water while they live much longer in distilled water. It is obvious that in 
these instances no change in the distribution of the fluids can occur, for the 
osmotic pressure of the fluid is unchanged. In other words the death of 
these animals in pure salt solution is due not to the physical action of the 
salt (salt action) but to the sodium ion exercising a deleterious effect on 
the n. This deleterious action may be neutralized by the addition of traces 
of salts of calcium or of some other bivalent elements, while the monovalent 
kations have no such antagonistic effects (Loeb). In the natural environ- 
ment of living cells both sodium and calcium are present, so that the toxic 
effect of sodium (see Calcium) can scarcely be observed except when small 
masses of tissue are thoroughly washed with salt solution ; as far as the 
higher animals are concerned, then, salt may be regarded as indifferent in 
itself and as acting only through changing the distribution of the fluids. 
And as isotonic solutions have no osmotic action, they are entirely inert. 

Water or very dilute salt solutions penetrate into the superficial cells 
of the Skin, which therefore become swollen and softened. Concen- 
trated solutions on the other hand rather tend to draw fluid from the 
surface cells, and this along with the passage of salt into them, causes 
some mild irritation. Neither salt nor water is absorbed into, the cir- 
culation through the skin in mammals. A much greater absorption 
into the superficial tissues occurs on less protected parts, such as the- 
cornea, which becomes white and clouded when strong salt solutions 
are applied to it. Similarly, either pure water or strong salt solution 
causes considerable pain and smarting in the nasal passages, or in 
wounds, from the disturbance of the normal relation of salt and fluid 
in the surface cells. Isotonic solutions on the other hand cause no 
pain. 

In the Mouth salt has a characteristic taste, and strong solutions act 
as astringents here and in the throat. In the Stomach its action is 
very much like that on other mucous membranes, hypotonic solutions 
causing swelling, while hypertonic solutions cause a withdrawal of fluid 
and a shrinking of the cells. This withdrawal of fluid and imbibition 
of salt may set up such irritation as to induce vomiting. 

The digestion in the stomach does not always seem to be improved 
by salt in the food, for even small quantities have been found to lessen 
the acidity of the gastric jnice, and the amount of albuminous food ab- 
sorbed from the alimentary canal in animals is but little altered when 
salt is added to the food. It is very possible, however, that a small 
quantity of salt in the food renders it more palatable in many instances, 



492 INORGANIC SALTS, Ad US AND J: ASKS. 

and thus increases the reflex flow of the gastric juice. (Compare Bitters, 
page 56.) Dapper finds that the hydrochloric acid of the stomach is 
increased in some persons, and diminished in others by mineral waters 
containing common salt as their chief ingredient. This is only to be 
explained by supposing that these waters have no effect on the secre- 
tion directly, but alter it by changing the nutrition of the gastric 
mucous membrane. 

Salt solutions are Absorbed both in the stomach and bowel, but con- 
siderable difference of opinion exists as to the means by which this is 
accomplished. An attempt has been made to explain absorption by 
the action of the known physical processes, such as diffusion, osmosis 
and filtration, but these seem quite inadequate without the assumption 
that there is a constant tendency for fluids and for some salts to pass 
inwards from the lumen of the bowel and stomach. This tendency 
may be opposed or strengthened by the osmotic pressure. Thus hypo- 
tonic solutions and water are absorbed rapidly, because here not only 
is the natural flow inwards, but the osmotic current is in the same 
direction, the fluid being of lower osmotic pressure than the blood 
serum ; but even pure water appears not to be absorbed from the 
stomach until it has acquired a certain content of salts which diffuse 
into it from the blood. In solutions of equal osmotic pressure with 
the blood serum the absorption is slower, because here the natural flow 
alone is active, while hypertonic solutions are still more slowly absorbed 
or may even be increased at first, because the osmotic pressure acts in 
the opposite direction from the natural flow. Accordingly, while hypo- 
tonic and isotonic solutions disappear rapidly, the absorption of the 
stronger solutions may be preceded by a period in which the fluid of 
the bowel actually increases, water diffusing into it from the blood. 
At the same time the salt is being absorbed, and the solution eventually 
becomes isotonic, and is absorbed. The absorption from the bowel is 
very similar to that described by Hofmeister in gelatine plates, and it 
is possible that the unexplained tendency for fluids to pass inwards 
may be due to some " affinity " between the salts and the colloids of 
the bowel wall. 

The Blood and Lymph are in turn affected by these processes. When 
hypotonic solutions pass into the blood from the bowel, the proj>ortion 
of solids and liquid is of course changed, and fewer corpuscles and less 
solid matter are found in the cubic millimetre than normally (hydre- 
mia). On the other hand, when strong salt solutions in the bowel 
cause the effusion of fluid, the blood becomes more concentrated than 
in ordinary conditions. After the reabsorption of the fluid, the normal 
balance of plasma and corpuscles must be restored, and to effect this 
currents are set up between the blood and the fluid of the surrounding 
lymph. These currents have been investigated by the injection of salt 
solutions directly into the blood, and not by their absorption from the 
bowel, but the processes probably resemble each other in their chief 
features. When the blood is rendered hypertonic by the injection 
of strong salt solution, the lymph at once begins to pour into the blood 



SODIUM CHLORIDE AND WATER. 493 

vessels by osmotic attraction, and this leads to hydremia and increased 
capillary pressure, the arterial tension remaining unchanged. This 
augmentation of the capillary pressure in turn induces a flow of lymph 
from the blood vessels into the lymph spaces. 

The flow of lymph from the blood vessels is first, therefore, dimin- 
ished in amount by the presence of salt in the intestine and blood, and 
then increased again by the high capillary pressure. This interchange 
between the blood and lymph is continued, because as the salt is ex- 
creted by the kidneys and other excretory glands, a continual varia- 
tion in the osmotic pressure of both blood and lymph occurs. 

The details of the changes between the blood and lymph under the 
action of salt and water are still obscure, but there is no question that 
the absorption of either of these leads to an augmentation of the normal 
exchange of these fluids. In particular, it is still undecided whether 
the cells of the vessels possess a secretory function similar to that of 
the secretory glands, or whether the whole process may be attributed 
to variations of osmotic pressure and filtration. 

The changes in the blood and lymph are followed by an increased 
activity of the Excretory Organs. Thus the urine l is much augmented 
by the injection of salt solution into the blood, less so by the absorption 
of water or salt solution from the stomach and bowel. A good deal of 
discussion has been carried on in recent years as to the cause of the 
diuresis from salts and water, and some authorities hold that the 
presence of salt in excess in the blood stimulates the renal cells much 
in the same way as caffeine. But a more plausible explanation is that 
the greater volume of the blood, following the absorption of the 
fluid and the increased flow of lymph, results in an increase in the 
capillary pressure in the glomerulus and this in turn promotes the 
escape of fluid into the capsule. A more rapid flow through the 
tubules follows, and the glomerular secretion lies in them for a shorter 
time, so that there is less tendency for its constituents to be reabsorbed 
into the blood vessels ; the fluid reaching the ureters is accordingly 
increased and the dissolved salts and urea are also augmented ; those 
constituents which in ordinary circumstances are absorbed most readily 
by the epithelium of the tubules are increased more than the others, so 
that the chlorides, and the potassium and sodium of the urine rise 
much more than the urea, phosphates or sulphates even when the 
diuresis is due to the absorption of water. Any other diffusible body 
increases the urine in the same way as salt, and urea has therefore been 
suggested as a diuretic ; it differs from salt in the difficulty with which 
it is absorbed from the tubules of the kidney and this further retards 
the absorption of the fluid, so that urea may probably have a more 
powerful diuretic action than sodium chloride. 

Other secretions, such as the saliva, are increased by salt, and this 

^ l The following explanation of the diuresis is based upon the theory that all the con- 
stituents of the urine are excreted by the glomerulus, and that some of them, notablv 
much of the fluid and the alkali chlorides, are reabsorbed in passing through the 
tubules. See Journ. of Physiol., xxvii. , p. 429. 



494 INORGANIC SALTS, ACIDS AND BASKS. 

not only by a reflex from the mouth, but also because some of the salt 
is excreted by the salivary glands. 

When very large amounts of isotonic salt solution arc thrown into 
the blood, the organism may have difficulty in excreting it rapidly 
enough, and the tissues are therefore found to be swollen and cedema- 
tous in some parts of the body. 

When salt solution is injected into the serous cavities or into the 
lymph spaces, absorption occurs in the same way as from the alimentary 
canal, except that in the case of the serous cavities osmosis seems to 
play a greater, and the other forces a smaller role, than in the stomach 
and intestine. 

The administration of large quantities of fluid, either as water or 
as dilute salt solution, might be expected to have some effect on the 
general Tissue Change, through the increased movement of the lymph 
flushing out the cells and leading to a more complete removal of the 
waste products. As a matter of fact, some increase in the nitrogen 
and sulphur eliminated in the urine has been observed under the use 
of large quantities of water, but it is impossible to estimate at present 
how far this may be due to the diuresis alone ; in any case the increase 
is not by any means so large as is often believed, as it only amounts to 
some 5 per cent., or less. Any salt solution causing an acceleration in 
the movement of the fluids of the body must tend to facilitate the 
excretion of the waste products in the same way, but some recent 
investigations indicate that in addition salt tends to lessen the proteid 
metabolism through acting directly on the cells ; this action is so slight, 
however, that the resulting fall in the nitrogen eliminated is concealed 
by the increase caused by the more complete flushing and diuresis. 
The amount of proteids and fats absorbed from the alimentary tract 
does not appear to be altered by the administration of large amounts 
of water (Edsall). 

Strong salt solutions injected into animals either hypodermically or intra- 
venously sometimes prove fatal, apparently from the withdrawal of fluid 
from the central nervous system. The symptoms in mammals are increas- 
ing lassitude and weakness, with augmented reflex excitability, tremors, and 
finally convulsions. The circulation is only slightly affected until just before 
death, when the blood-pressure falls suddenly. The red blood cells are 
found to be much shrunken, and according to Heinz, form thrombi in many 
vessels. Haemorrhages are found in different organs, the lungs are cedema- 
tous, and the intestinal mucous membrane is swollen and congested. 

The Salts of the Urine are increased by diuresis from any cause as 
has been stated ; both sodium and potassium are augmented but espe- 
cially the sodium which is present in larger proportions in the serum 
and therefore forms a larger constituent of the glomerular secretion. 
This increase in the sodium salts is of course particularly marked when 
diuresis is induced by common salt, but when potassium salts increase 
the urine, the sodium also generally predominates in it and this would 
eventually lead to the loss of all the sodium in the blood of herbivora, 
whose food contains large quantities of potassium ; but after a certain 



SODIUM CHLORIDE AND WATER. 495 

amount of sodium has been lost, potassium causes no further excretion 
so that the tissues apparently protect themselves from the total loss N of 
sodium chloride, which would be fatal to them. 

Bunge states that in both man and animals a diet 1 ich in potassium causes 
an appetite for common salt, while a diet which does not contain an excess 
of potash, does not develop this desire. Thus herbivorous animals and 
agricultural peoples seek for salt, because vegetable foods contain large 
quantities of potassium, while the carnivora and the hunting peoples require 
no salt and often have a distaste for it, owing to their food containing a larger 
relative proportion of sodium salts. This instinctive appetite he regards as 
a means by which nature protects the tissues from excessive loss of sodium. 
Some doubt has recently been thrown on this explanation of the desire for 
salt by Lapicque, who discovered some African races living on vegetable sub- 
stances alone, and using the ashes of the plants, which contain more potas- 
sium than sodium, as civilized peoples use ordinary salt. He holds, there- 
fore, that salt is merely of value as a flavoring agent. 

Therapeutic Uses. — Water and salt are rarely or never prescribed as 
such, but are used to a very large extent in medicine, and great virtues 
have been ascribed to them in a number of pathological conditions. 

They are used for their local action, and for the supposed alterations 
in the tissue-change and in the excretions produced by them after their 
absorption into the blood. In general, patients are sent to watering 
places and baths, and the success of the treatment is to a considerable 
extent due to the climatic conditions, the change in the habits of life, 
the dietetic treatment, and the rest from everyday occupations. At 
the same time the drinking of large quantities of weak salt solutions, 
and the constant bathing in somewhat irritating fluids, may exercise a 
therapeutic action in many cases, and may at any rate aid the hygienic 
conditions. Whether the water contains salt or not, it must be remem- 
bered that in bathing the action is a purely local one, for neither the 
salt nor the water is absorbed. The slightly irritant effect on the skin 
may, however, improve its circulation and nutrition, and thereby be 
efficacious in some skin diseases. By continued use, the sensitiveness 
of the skin vessels to heat and cold may also possibly be deadened. 
Remarkable effects on the tissue change have been alleged to be pro- 
duced by bathing in strong salt solutions, owing to their counter- 
irritant action. For example, the excretion of urea and the oxidation 
in the body are often said to be much increased, but these results have 
not been confirmed after further experience. Special baths are very 
frequently recommended for some diseases, but it must be remembered 
that the action is due to the salt-action ; the greater the concentration, 
the greater is the effect on the skin, and it is of no importance which 
of the neutral salts is in the solution, or whether small traces of iron 
or other metals are present ; alkaline baths are more stimulant than 
others. 

In diseases of the stomach the drinking of large quantities of water 
or of weak salt solutions may also be beneficial. The action is similar 
to that on the skin — a mild stimulation, owing to the swelling up of 
the more superficial cells of the epithelium and the increased move- 



496 INORGANIC SALTS, ACIDS AND BASKS. 

ment of the fluid in them and in the deeper layers. In some cases of 
insomnia hot water sometimes causes sleep, probably by causing dila- 
tation of the gastric vessels, and thereby withdrawing the blood from 
the brain. 

In many diseases in which the symptoms point to a disorder of the 
metabolism, water and salt solutions are advised. Thus gout and 
rheumatism are frequently treated by sending the patients to watering 
places, on the theory that the tissues are washed out thoroughly, and 
the waste products thus removed. As a matter of fact, the more recent 
work in this direction shows that large quantities of water and dilute 
salt solutions have little or no effect on the uric acid excretion, which 
was formerly believed to be much diminished. This fact does not 
necessarily involve the inference that the treatment is erroneous, for it 
is now generally recognized that gout is not really due to the failure 
of the uric acid excretion. Many cases are unquestionably benefited 
by the springs, although it may be questioned how much of the 
improvement is due to the water taken, and how much of it ought to 
be ascribed to the changed conditions of life. 

The bath treatment has been recommended for numerous diseases 
in which the salt and water could not possibly have any beneficial 
action, and in which the remedial agent is the climate, and perhaps the 
faith of the patient in the water. Belief in the healing power of cer- 
tain natural waters is one of the most ancient of all therapeutic 
theories, is found among altogether uncivilized peoples, and has been 
incorporated in many religions. It is not to be wondered at that in 
some nervous disorders the faith of the patient and auto-suggestion 
perform some marvelous " cures." 

In obesity the drinking of some waters, such as that of Kissingen 
and Homburg, has been advised. These waters contain from 0.2-1.4 
per cent, sodium chloride. This can scarcely be brought into agree- 
ment with Oertel's treatment of obesity by lessening the amount of 
water taken. At the same time the relation between obesity and 
water absorption is still very obscure, for while OertePs treatment 
undoubtedly lowers the weight in many cases, a well-known Tule in 
fattening animals is to reduce their water consumption to a minimum. 

Salt in solid form or in strong solution is used occasionally as an 
emetic in cases of emergency, as in poisoning, and generally produces 
vomiting rapidly, owing to the irritant action on the stomach. In 
nitrate of silver poisoning it arrests the corrosive action by the forma- 
tion of the insoluble silver chloride. 

Salt solution is often used instead of water in enemata and possesses 
when concentrated an irritant action on the bowel, producing peri- 
stalsis. Strong solutions are sometimes thrown into the rectum to 
destroy round worms. 

Isotonic salt solutions (0.6-0.9 per cent.) are often administered 
when the body has lost much fluid, as they are rapidly absorbed and 
are devoid of irritant action ; thus in haemorrhage these solutions 
are injected subcutaneously, intravenously, or per rectum. A rapid 



SODIUM CHLORIDE AND WATER. 497 

improvement in the circulation follows, and this has given rise to the 
erroneous opinion that such saline infusions stimulate the heart directly 
as well as by the mechanical effect of the increase in the fluids of the 
body ; this theory has led to infusions being made in weakness of 
the heart from other causes than haemorrhage. Some of the symp- 
toms of cholera are believed to be due to the loss of fluid, and these 
are said to be relieved by the injection of salt solutions, though the 
mortality does not seem materially altered. The intravenous and sub- 
cutanous injection of salt solution has been recommended in uraemia 
and similar intoxications, with the idea of washing out the poisons 
through the kidneys ; the same results can often be obtained by drink- 
ing large quantities of water. There is still some question as to whether 
the infusion of salt, solution is really remedial in loss of blood, and the 
latest investigator of the matter, Feis, comes to the conclusion that it 
is of little or no benefit. The hypodermic injection of large quantities 
of isotonic salt solution is said by Biernacki to have effects which only 
pass off in some 6—8 days in animals. The blood was at first much 
diluted, but afterwards became very concentrated and after a few days 
a considerable number of the red cells were found in a state of disin- 
tegration, and the haemoglobin thus liberated was distributed through 
the plasma until it was finally excreted in the urine. The animals 
did not seem to suffer from the treatment, but his results indicate that 
the injection of large quantities of salt solutions is by no means the 
harmless proceeding which it is generally believed to be. 

Isotonic salt solutions are used in surgery to wash out the peritoneal 
cavity, which would be injured by distilled water. 

Preparations. 

Sodii Chloridum (U. S. P., B. P.), common salt. 

Aqua (U. S. P.). 

Aqua Destillata (TJ. S. P., B. P.). 

Bibliography. 

See Salt- Action (page 489) and Saline Cathartics. 

Heidenhain. Pfluger's Arch., xlix., p. 209; lvi., p. 579. 

Starling, etc. Journal of Physiol., xvi., xvii., xviii. 

Cohnstein. Pfluger's Arch., lix., lxii., lxiii. Virchow's Arch., cxxxv., p. 514. 

Mayer. Ztschr. f. klin. Med., ii., p. 34; iii., p. 82. 

Leathes. Jour, of Phys., xix., p. 1. 

Mendel. Ibid., xix., p. 227. 

Orloiv. Pfluger's Arch., lix., p. 170. 

v. Limbeck. Arch. f. exp. Path. u. Pharm., xxv., p. 69. 

Dreser. Ibid., xxix., p. 303. 

Reichmann. Ibid., xxiv., p. 78. 

Limbourg. Ibid., xxiv., p. 342. 

Munzer. Ibid., xli., p. 74. 

Loeb. Amer. Jour, of Phys., iii., pp. 327, 383, 434. Pfluger's Arch., lxxxviii., p. 
68. 

Gabriel. Ztschr. f. Biol., xi., p. 554. 

Heinz. Virchow's Arch., cxxii., p. 100. 

Bange. Lehrbuch der phys. u. path. Cheniie, 2d ed., p. 107. Ztschr. f. Biologie, 
xli., p. 484. 

Grawitz. Zts. f. klin. Med., xxii., p. 417. 

Ludwig. Centralbl. f. inn. Med., 1896, Nos. 45 and 46. 
32 



498 INORGANIC SALTS, ACIDS AND BASKS. 

Feis. Virchow's Arch., cxxxviii., p. 75. 

JBiemacki. Ztschr. f. klin. Med., xix., SuppL, p. 49. 

Straub. Ztschr. f. Biologie, xxxvii., p. 527 ; xxxviii., p. 537. 

Magnus u. Gottlieb. Arch. f. exp. Path. u. Pharm., xliv. and xlv. 

Lenhartz. Deutsch. Arch. f. klin. Med., lxiv., p. 189. 

Leonfacher. Mittheil. a. d. Grenzgebiete, \l., p. 321. 

Taylor, Frazier, Edsall. Pepper Laboratory Keports, Philadelphia, 1900, pp. 356, 368. 

Sollmann. Arch. f. exp. Path. u. Pharm., xlvi., p. 1. 

II. POTASSIUM SALTS. 

The effects of potassium in the organism can best be studied by ad- 
ministering the chloride, as the CI ion is practically devoid of action 
and the symptoms induced by potassic chloride must therefore be due 
either to the " salt-action " or to the potassium. The salt-action can 
be discounted by comparing the symptoms with those of an isotonic 
solution of sodium chloride, and when this is done it is found that 
potassium has a distinctly poisonous action, which is chiefly manifested 
in depression of the central nervous system and of the heart. 

In the frog the central action is shown by the spontaneous move- 
ments becoming weak and slowly performed, and by their completely 
disappearing much earlier than in sodium chloride experiments. In 
mammals the chief nervous symptoms are great muscular weakness and 
apathy. The respiration becomes rapid and labored, probably from 
the anaemia of the centres, and death is often preceded by weak as- 
phyxial convulsions. 

The depression of the heart is shown in the frog by weakness, slow- 
ness and irregularity when chloride of potassium is injected subcu- 
taneously, but is more clearly demonstrated by the rapid failure of an 
excised heart when a chloride of potassium solution is perfused through 
it. An isotonic solution of common salt also brings the heart to stand- 
still after a time, but potassic chloride acts very much more quickly, 
and, in fact, the former may restore the heart beat after it has been 
stopped by potassium, which proves conclusively that the latter has a 
specific poisonous action in addition to any salt-action. Ringer, how- 
ever, found that the beat of the frog's heart perfused with a solution 
of common salt was not so satisfactory as that of one perfused with 
the same solution to which some potassic salt had been added, because, 
as has been already mentioned, the proteids of the heart must contain 
potassium, and when this is substituted by sodium, as is the case when 
there is no potassium in the perfusion fluid, the muscle becomes in- 
capable of normal contraction. (See Calcium.) 

The mammalian heart is also injured by the action of potassium 
when the salt is administered in large quantities, as is shown by the 
pulse becoming much slower and weaker and by a sudden fall of blood- 
pressure ; an acceleration of the pulse is often observed at first. The 
poisonous action of potash on the heart has given rise to exaggerated 
apprehensions of the danger of using its salts in therapeutics, and it 
may therefore be noted that potassium has practically no effect on the 
heart when given by the stomach, and that very much larger quantities 
of potash are taken daily in the food by thousands of persons than are 



POTASSIUM SALTS. 499 

ever prescribed in medicine. Bunge estimates the amount of potash in 
the food of some classes at 50-100 grms. (1J-3 oz.) per day. The 
absence of effects from the potassium ion when the salts are taken by 
the mouth is due to their rapid excretion in the urine. 

The failure of the heart is the cause of death in mammals when 
potassium salts are injected into a vein, the respiration and the reflexes 
often persisting for a few seconds afterwards. 

Potassium has some action on muscle in the frog, the contraction seeming 
to be somewhat greater in height, though shorter in length, and there being 
less tendency to contracture. Muscle exposed in a solution of potassic chlo- 
ride dies very much sooner than in an isotonic solution of sodium chloride. 

Chloride of potash has also some depressant action on the peripheral 
nerves, for they lose their irritability rapidly when they are exposed to its 
solutions. A concentrated solution applied to an exposed nerve causes con- 
tractions of the muscles which are supplied by it, but these are weaker 
and last a much shorter time than those elicited by a similar solution of 
common salt. This is explained by the depressant action of the potassium 
opposing the irritation which it induces through its salt-action. This effect 
on the nerves has been used by Pohl to explain a curious observation made 
by Nothnagel, who' found that a strong solution of chloride of sodium ap- 
plied to the peritoneal surface of the rabbit's intestine, causes a local con- 
traction, followed by an upward peristaltic wave, while a similar solution of 
a potassium salt induces only local contraction. Pohl supposes that in the 
case of the sodium salt the peristaltic wave is caused by nerve stimulation, 
while the potassium depresses the nerve so much that it is unable to carry 
the impulses, and the contraction therefore remains local. 

The absorption of potassium salts is followed by the same changes in the 
movement of the fluids of the body as have been described in the case of 
sodium chloride (page 493). This generally results in diuresis with an in- 
crease in the potassium and the sodium and chloride in the urine. It is often 
stated that the potassium salts induce a more marked increase in the urine 
than those of sodium, but this is not based on any satisfactory measurements ; 
another statement which requires confirmation, is that strong solutions of po- 
tassic chloride are more irritating to the stomach and also in the subcutane- 
ous tissues, than those of sodium chloride ; this would indicate that potassium 
has a specific irritant action apart from its salt-action, which is not unlikely, 
although it cannot be said to have been demonstrated satisfactorily as yet. 

Bibliography. 

See also Salt-action (p. 489) and Sodium Chloride (p. 497). 

Guitmann. Berl. klin. Woch., 1865. 

Grandeau. Journ. de l'Anat., 1864, p. 378. 

Bunge. PA tiger's Arch., iv., p. 235. Handbuch der physiol. Chem., p. 107. 

Dehn. Pfltiger's Arch., xiii., p. 353. 

Fidel. Ibid., xxxv., p. 157. 

Pohl. Arch. f. exp. Path. u. Pharm., xxxiv., p. 95. 

Limbourg. Ibid., xxiv., p. 342. 

Ringer. See the bibliography given under Calcium. 

Dogiel. Centralbl. f. d. med. Wiss., 1892, p. 354. 

Brunton and Cash. Phil. Trans. Koy. Soc, 1884, Part 1, p. 197. 

Lithium, Caesium, Rubidium. 

In regard to the action of the rarer alkalies. Lithium, Caesium and Rubid- 
ium, 1 comparatively little is known. They seem to have some effect in de- 

1 The still rarer metals Yttrium, Erbium, Beryllium, Didymium and Lanthanum 
have scarcely received examination except at the hands of Brunton and Cash, and are 
not of sufficient importance to require further mention here. 



500 INORGANIC SALTS, ACIDS AND BASES. 

pressing the spinal cord in the frog, but it is uncertain whether this is, like 
the action of sodium chloride, merely due to the presence of large quantities 
of salts in the body, or whether they have a specific action on the nerve cells. 
Lithium seems to have some further depressant action on the motor nerves 
and to weaken the muscular contraction. It acts much less powerfully on 
the mammalian heart than potassium, but has some effect in weakening it. 
Its chief effects are exercised in the alimentary tract, for gastro-enteritis and 
extravasations of blood into the stomach and bowel are induced by its sub- 
cutaneous or intravenous injection and these are the cause of death in fatal 
poisoning in animals. Such violent effects are less easily elicited by the ad- 
ministration of lithium by the mouth, though vomiting and purging have been 
caused in animals by this method also. Some of the lithium is excreted in the 
bowel, and in this respect this metal appears to form a contrast to potassium 
and sodium and to resemble rather the group of alkaline earths. 

Rubidium seems to act on the frog's heart in the s-ame way as potassium, 
while caesium is less poisonous, and differs from it entirely in some points of 
detail. In their action on striped and unstriped muscular tissue they seem 
to stand between potassium and sodium. Many attempts have been made 
to demonstrate that the relative toxicity of the alkaline metals bears some 
relation to their atomic weights, and in many instances the intensity of their 
action certainly seems to vary according to these, but the subject is not yet 
sufficiently developed to admit of a general statement. 

Bibliography. 

Husemann. Gottingen Nachrichten, 1875, p. 97. 
Krumhoff. Inaug. Diss., Gottingen, 1884. 
Ringer. Jour, of Phys., iv., p. 370. 

Dietrich u. Harnack. Arch. f. exp. Path. u. Pharm., xix., p. 153. 
Bruntonand Cash. Phil. Trans. Roy. Soc, 1884, p. 197. 
Binet. Comptes rendus de l'Academie, cxv., p. 251. 

Richet. Arch, de Physiol., 1886, i., p. 101. Trav. d. Laborat. de Physiol., ii., p. 
398, 1893. 

Blumenthal. Pfluger's Arch., lxii., p. 513. 
Winkler. Ibid., lxxi., p. 395. 

III. AMMONIUM. 

Although ammonium is not a metal, its behavior in the body resem- 
bles in many points that of the fixed alkalies, and it may therefore 
best be studied along Avith them. The ordinary solutions of ammonia, 
and the gas itself are possessed of powerful irritant properties, and its 
general action can be determined only by the examination of those of 
its salts in which, as in ammonium chloride, the effects of the anion 
can be neglected. The action of chloride of ammonium is due to the 
specific action of the base and to the salt-action. 

Action. — Its most striking effect is the stimulation of the Central 
Nervous System, which is induced when it is injected subcutaneously 
or intravenously. The reflex irritability is much increased, and this 
may be followed by tetanic convulsions both in frogs and mammals. 
These convulsions persist after division of the cervical spinal cord and 
destruction of the medulla oblongata and brain, and are evidently 
caused by changes in the spinal cord, similar to those met with in 
strychnine poisoning. According to Yourinsky, the increased reflex 
and the convulsions are preceded by a short stage of depression in the 
frog and pigeon, but this depression is not observed when the parts of 



AMMONIUM. 501 

the central nervous system above the cord are destroyed in the frog, 
or when the cerebrum is removed in the pigeon. He holds that the 
brain is first stimulated, and that this action inhibits the reflexes, but 
that as the stimulation passes downwards, the spinal cord is acted on 
in turn and the reflexes are exaggerated. The medullary centres are 
also involved, for the respiration very often ceases for a moment, and 
then becomes very much accelerated, and in some instances deeper. 
The cause of the altered breathing is a stimulation of the respiratory 
centre ; the preliminary pause is attributed by some to action on the 
vagus ends in the lungs, but this is denied by others, and it seems 
possible that it is due to excessive stimulation of the respiratory 
centre. 

The blood-pressure rises from contraction of the peripheral arterioles, 
induced by stimulation of the vaso-motor centre, while the heart is 
sometimes slowed from increased activity of the inhibitory centre, but is 
said to be accelerated in other cases ; whether this arises from action 
on the cardiac muscle or on the accelerator centre is still unknown. 

During the convulsions, the respiration is arrested and the blood- 
pressure becomes extremely high. If large enough quantities be in- 
jected, the stimulation is followed by paralysis of the central nervous 
system and the animal dies of asphyxia, but if artificial respiration be 
carried on it recovers rapidly, from the salt being changed to an inac- 
tive substance in the tissues. 

In the frog ammonium chloride tends to paralyze the terminations of 
the Motor Nerves, but little or no such action is met with in mammals. 
This marked cnrara-like action differentiates the ammonium tetanus of 
the frog from that seen under strychnine, as the spasms last a shorter 
time, and soon become weaker from the impulses failing to reach the 
muscles through the depressed terminations. The Muscles themselves 
are also acted on by ammonium in much the same way as by potassium, 
although in the case of ammonium a preliminary stage of somewhat 
augmented irritability has been observed by some investigators. Am- 
monium chloride is generally credited with acting on the Secretions of 
the stomach and of the bronchial mucous membrane, which it is said 
to render more fluid and less tenacious, and at the same time to increase 
considerably. 1 No explanation of this effect on the mucous secretion 
has been offered, and ammonia does not seem to be excreted by the 
lungs, nor has it been found in the bronchial secretion. 

Ammonium salts penetrate the cells of the body more freely than the 
salts of the fixed alkalies. For this reason solutions of ammonium chlo- 
ride are absorbed more rapidly from the stomach and intestine than those 
of sodium or potassium chloride, and it has been shown that they perme- 
ate the blood cells with still greater freedom. In fact, solutions of 
the chloride of ammonia meet with little more resistance in entering 
the red blood corpuscles than does distilled water. If, however, am- 
monium be combined with a non-permeating ion, it fails to penetrate 

1 Rossbach states that the injection of the chloride into the vein of an animal lessens 
the bronchial secretion. 



502 INORGANIC SALTS, ACIDS AND BASES. 

Thus the sulphate of ammonium is slightly cathartic, although less so 
than the sulphates of the fixed alkalies, and it also fails to permeate 
the red blood cells. (See Saline Cathartics.) 

When ammonium salts are taken by the mouth, they have little or 
no tendency to cause symptoms from either the central nervous system 
or the heart. No case is known in which convulsive attacks could be 
shown to be due to the direct action on the central nervous system in 
man, and it is very doubtful whether the circulation is affected at all. 
In some cases of poisoning with ammonium hydrate, convulsions have 
occurred, but these seem to be due to the violent local action of the 
caustic alkali. The chloride of ammonium may induce irritation and 
vomiting when taken in large quantities into the stomach, but only 
through its action as a salt. 

Ammonium is changed to urea in the body and is Excreted in this 
form in the urine. This transformation, which probably takes place in 
the liver chiefly, proceeds very rapidly, so that considerable quantities 
of some salts may be injected slowly into a vein without inducing any 
symptoms whatever. The urea in the urine would therefore tend to 
be increased by ammonia if other factors were not involved, and as a 
matter of fact this occurs in the herbivora. In carnivorous animals and 
in man, on the other hand, some of the salts of ammonium increase the ex- 
cretion of urea, while others apparently increase the ammonium salts in 
the urine. Thus the carbonate or acetate of ammonium is excreted as 
urea, while the chloride appears to be excreted unchanged. This differ- 
ence in the behavior of the ammonium salts is more apparent than real, 
however. As a matter of fact the ammonia is excreted as urea in each 
case, but the acid with which it is in combination may conceal this. In 
the case of the carbonate no acid is freed, and the same is true of the 
acetate, which is oxidized to the carbonate in the tissues. When, how- 
ever, urea is formed from ammonium chloride, hydrochloric acid is lib- 
erated in the tissues and would act as a poison, were it not neutralized at 
once by ammonia being formed in the tissues themselves. It is then ex- 
creted by the urine in combination with this freshly formed ammonia, 1 
while that with which it was formerly combined appears as urea. The 
formation of ammonia in the tissues, however, withdraws some nitrogen 
which would ordinarily have formed urea, so that the net result is that 
the urea excretion is little changed, while the ammonia of the urine is 
much increased. The carnivora therefore neutralize the hydrochloric 
acid with freshly formed ammonia. The herbivora on the other hand 
neutralize it with fixed alkali, so that the administration of ammonia 
always increases the urea excreted by them, while little or no ammo- 
nia appears in the urine ; at the same time the fixed alkalies of the 
blood tend to become neutralized, and this may give rise to serious 
symptoms. (See Acids.) 

The urine is often increased by the exhibition of ammonium salts, but 
not always. It is to be noted that, while the alkaline salts of the fixed 

1 In some cases apparently the hydrochloric acid is not excreted in this way at once, 
but goes to increase the acidity of the gastric juice. 



AMMONIUM. 503 

alkalies render the urine less acid or even alkaline, ammonium salts 
have no such effect, because they are excreted as urea. 

In birds and reptiles, ammonia is apparently excreted as uric acid. 

The Substituted Ammonias of the methane series, such as methylamine, 
and some of those of the aromatic series resemble ammonia in their general 
effects, but the stimulation of the central nervous system is not often so 
marked a feature. In general terms, those compounds in which one hydro- 
gen atom is substituted, tend to cause greater nervous stimulation than those 
in which two or three such substitutions are made, while this action is again 
more prominent in those in which four alkyl groups are combined with the 
nitrogen. In addition, most of these compounds seem to have a more depres- 
sant action on the central nervous system afterwards than ammonia, and they 
all tend to weaken and eventually paralyze the terminations of the motor 
nerves. 

The ammonium bases formed from the natural alkaloids appear to have 
less action on the central nervous system, but act like curara on the termina- 
tions of the motor nerves. (See page 260.) 

Preparations. 

Ammonii Chloridum (U. S. P., B. P.) (NH 4 C1), 0.3-1 G. (5-15 grs.), in 
solution. 

Trochisci Ammonii Chloridi (U. S. P.), each containing 0.1 G. (2 grs.) of 
ammonium chloride with 0.25 G. (4 grs.) of liquorice extract and some syrup 
of Tolu. 

Therapeutic Uses. — The chloride is prescribed chiefly for its effects 
on the respiratory mucous membranes, and is a very common constit- 
uent of expectorant mixtures for bronchitis and catarrh. The lozenge 
is often used for sore throat, and chloride of ammonium solutions are 
occasionally inhaled or sprayed into the throat. It has also been pre- 
scribed in gastric catarrh with benefit in some cases, but whether this 
is due to its acting on the mucous secretion, or to its increasing the 
acidity of the gastric juice is unknown. 

Ammonium chloride and the chloride of trimethylammonium were at 
one time advised in rheumatism, but have proved useless in this disease. 

Bibliography. 

On the Action of the Ammonium ion. 

Lange. Arch. f. exp. Path. u. Pharra., ii., p. 364. 

Feltz et Ritter. Journ. de l'Anat. et de la Physiol., 1874, p. 326. 

Funke. Pfltiger's Arch., ix., p. 416. 

Binz. Centralbl. f. klin. Med., 1888, p. 25. 

Yourinsky. Arch. d. Sciences biolog., iii., p. 260. 

Bossbach. Festschr. zur dritten Saecularfeier, Wiirzberg, 1882, i., p. 85. 

Formanek. Arch, internal, de pharmakodyn., vii., p. 229. 

On the fate of ammonia in the body. 

Schmiedeberg. Arch. f. exp. Path., viii., p. 1. 

Hallervorden. Ibid., x., p. 125. 

Coranda. Ibid., xii., p. 76. 

Knieriem. Zeitschr. f. Biol., x., p. 263. 

Salkowski. Zeitschr. f. physiol. Cliem., i., p. 1. 

Feder. Zeitschr. f. Biol., xiii., p. 256. 

Marfori. Arch. f. exp. Path. u. Pharm., xxxiii., p. 71. 

Rumpf u. Kleine. Zts. f. Biol., xxxiv., p. 65. 

Pohl u. Munzer. Arch. f. exp. Path. u. Pharm., xliii., p. 28. 



504 INORGANIC SALTS, ACIDS AND BASES. 

On the action of substituted ammonias. 

Brunton and Cash. Phil. Trans. Roy. Soc, 1884, i., p. 197. 
Nebelthau. Arch. f. exp. Path. u. Pharm., xxxvi., p. 451. 

IV. BROMIDES. 

It was formerly widely believed that the bromides had no further 
action than the chlorides, and that any effects observed from potassium 
bromide were due to the potassium ion, the bromide ion being indif- 
ferent. There is now no question, however, that the bromides have 
distinctive effects, for the bromides of potassium, sodium, lithium, and 
other metals induce changes in the central nervous system, which are 
not elicited by the chlorides. At the same time the bromide action is 
comparatively weak, and the basic part of the salt has therefore con- 
siderable influence on the action. 

Symptoms. — The bromide of potassium is the salt most generally 
used, and its action has been more carefully described than that of the 
other bromides. 

In the Alimentary Tract it acts in the same way as the chloride of 
sodium, possessing a bitter salt taste and inducing salivation and 
thirst, and in large quantities, irritation of the stomach, nausea and 
vomiting. Occasionally diarrhoea has been observed from concen- 
trated solutions reaching the intestine. 

General Symptoms. — Apart from these results of local irritation, the 
first symptom is often a dull, heavy headache, with a feeling of lassi- 
tude, fatigue, disinclination for exertion, mental or physical, and often 
muscular weakness. Thought is slow and confused, the memory is 
indistinct, ideas are put into words with difficulty and the speech is 
accordingly slow and hesitating. External objects and movements are 
perceived, but arouse no interest in the patient, and very often this 
state of apathy passes into drowsiness and sleep. The bromides, how- 
ever, have not the sleep-compelling power of morphine or chloral, and 
the sleep is never very deep and is not refreshing, the patient some- 
times feeling dull and unfit for exertion after it, and some mental con- 
fusion often persisting for several hours after awaking. The reflexes 
are much depressed by large doses of bromide, so that touching the 
back of the throat does not induce nausea, although the sensation of 
touch may persist. The mucous membranes of the genito-urinary 
tract are also less sensitive, or rather their irritation is less liable to 
set up reflex movements. After very large doses of the bromides the 
conjunctiva may sometimes be touched without causing winking, and 
lessened sensation in the skin has been noted in some cases. 

The pulse is slow and weak after large doses and the respiration is 
also less active. An increase in the urine is often observed. 

Acute fatal poisoning with bromides has seldom or never occurred 
in man, but after enormous doses prolonged sleep or stupor has been 
seen, and confusion and apathy lasting for several days. 

When bromide is given repeatedly in large doses, a series of symp- 
toms is often induced to which the name of Bromism has been applied. 



BROMIDES. 505 

It occurs much more rapidly in some persons than in others, and may 
suddenly appear after the patient has been taking the drag for months 
without any untoward results. The commonest symptoms of bromism 
are shin eruptions of various kinds, very often commencing as acne of 
the face. In severe cases the pustules of acne may coalesce and form 
small abscesses, which are followed by ulcers. In other cases the skin 
affection partakes rather of the nature of a localized blush or erythema, 
and sometimes copper-colored blotches have been observed. Some dis- 
turbance of the digestion and loss of appetite is often met with from the 
local action of large quantities of the salt on the stomach. Affections 
of the respiratory passages are not produced so often by the bromides 
as by the iodides, but have been met with and consist in an increased 
secretion of mucus by the bronchial and nasal epithelium. The mental 
symptoms are merely exaggerations of those observed after one large 
dose. The memory is especially defective, sometimes sudden lapses 
occurring, sometimes a general inability to remember the most recent 
events being met with. The patient is indifferent to his surroundings, 
speaks slowly and stammers, mispronounces ordinary words, or misses 
several words out of a sentence. The gait is uncertain and tremor 
often accompanies any movement, the expression of the face is stupid 
and apathetic, and the eyes are heavy and lack lustre. 

These symptoms generally disappear on the withdrawal of the drug, 
but in his reduced condition the patient is of course liable to fall a 
victim to infectious disease, and in a number of cases of chronic 
bromide poisoning the immediate cause of death has been an attack 
of bronchitis or pneumonia. 

Action. — The effects of the bromides on animals have been the sub- 
ject of a large number of researches, but these have not been attended 
with success in most cases, because the investigators have almost 
always used the bromide of potassium. The action here is complicated 
by the potassium action as well as by the salt-action, and these are 
often sufficient to obscure the slight depression of the brain which is 
the really characteristic effect of the bromide ion. In the frog, for 
example, potassium chloride is capable of inducing depression of the 
central nervous system, and a certain amount of stupor is induced by 
the salt action of chloride of sodium. The slightly greater depression 
induced by the bromide may well be overlooked, therefore, and many 
investigators have concluded that the bromide ion is as inactive as the 
chloride. The typical bromide action may be induced with greater 
clearness in mammals by the use of sodium bromide in repeated doses, 
and in dogs symptoms of depression and imperfect coordination have 
been observed, and sometimes stupor and death from failure of the 
respiration. The most characteristic action, however, is obtained from 
the administration of the drug to patients, as the affection of the cen- 
tral nervous system is so slight after all but extreme doses, that in 
order to produce distinct symptoms in the less sensitive brain of the 
dog, quantities must be used which entail the additional complication 
induced by salt-action. 



506 INORGANIC SALTS, ACIDS AND BASES. 

The irritation of the throat and stomach, the nausea, vomiting, and 
rarer diarrhoea must be attributed for the most part to the action of 
the salt in withdrawing fluid from the mucous membranes, and may 
be avoided by the use of dilute solutions and by their administration 
when the stomach is full. 

The depression and other mental symptoms are due to a direct action 
on the Central Nervous System. Albertoni found that the irritability 
of the motor areas of the dog's brain was very distinctly reduced by 
the administration of bromides, and in particular that a stimulus which 
normally would have spread over a wide area and given rise to an 
epileptiform convulsion, caused only localized contractions after bro- 
mides, while convulsive poisons entirely failed to act. Loewald found 
some psychical processes, such as those involved in the addition of 
numbers, uninfluenced by bromides, while a series of figures could be 
learned by rote only with great difficulty ; he therefore considers that 
the action is limited to certain definite functions. 1 The reflexes are 
also reduced very considerably by bromides, and according to many 
observers this occurs in the frog before the spontaneous movements 
cease. This is explained by the passage of impulses from the sensory 
to the motor cells of the cord being interrupted, while the connection 
between the cerebral centres and the motor cells of the cord is main- 
tained intact. The reflexes in man are prevented or retarded also, the 
most striking instance being the absence of reflex nausea when the 
back of the throat is touched. The other reflexes are also reduced, 
especially those of the genital organs, those of the conjunctiva being 
less affected. While reflex movements cannot be elicited, .the sensa- 
tion often remains unimpaired, but after large doses a more or less 
complete anaesthesia is said to be produced. This anaesthesia extends 
to the skin when very large quantities are administered, and the cutar 
neous nerves are said to be rendered somewhat less acutely sensitive, 
when comparatively small doses are taken. 

The depression of the spinal reflexes effected by the bromides ren- 
ders -them antidotal to strychnine, which induces convulsions only when 
given in much larger quantities than are usually necessary. 

In addition to the ordinary reflexes, some special functions are de- 
pressed by the bromides. Thus the respiration becomes slower, and 
the sexual instincts are depressed or entirely suspended in many cases. 
Whether the latter is caused by action on the spinal cord or on the 
cerebral cortex is unknown. 

The action on the central nervous system is due to the bromide 

only, and not to the base with which it is combined. Thus, it may be 

elicited by the bromides of potassium, sodium, lithium or ammonium, 

while it is not induced by their chlorides. At the same time it seems 

probable that potassium bromide acts more strongly than the others/ 

because the bromide action is here supplemented by the depressant 

action of the base. 

1 Wiersma states that the perception of stimuli by the senses is actually facilitated 
by bromides, but this appears to be incompatible with universal clinical experience. 



BROMIDES. 507 

The bromide ion is not very poisonous to Nerve and Muscle, but it is 
not so nearly indifferent to them as the chloride ion, although no effects 
are elicited unless the bromide is applied directly to the exposed mus- 
cle or nerves. 

The Cardiac Effects, when present, are caused by the potassium com- 
ponent only, and are not elicited by the bromides of sodium and am- 
monium. The vessels of the pia mater are often found contracted from 
the action of bromides, and this has been supposed to account for the 
depression. It is probable, however, that this anaemia of the brain is 
analagous to that observed in sleep and it may therefore be the result 
and not the cause of the depression. The mental disturbance observed 
in bromism is so nearly related to that seen after a single large dose, 
that it is unnecessary to enter into any explanation of it here. 

The Skin Eruptions have usually been attributed to the excretion of 
bromide through the cutaneous glands, and seem to arise in the great 
majority of cases from the glands, and in fact generally remain con- 
fined to them. Bromide has been found in the acne pustules, and it is 
quite conceivable that it may act as an irritant here, especially when 
the secretion becomes acid from decomposition. 

The Temperature of animals is often said to be reduced by the bro- 
mide ; this may be explained by the lessened movement. 

Excretion. — The bromides are rapidly absorbed by the mucous 
membranes, and some bromide reaction can be obtained from the urine 
a few minutes after they have reached the stomach, but the great mass 
of the drug is very slowly excreted. When the treatment is continued, 
the bromide therefore tends to accumulate in the body, but the pro- 
portion excreted rises with the increase of the salt in the blood, until 
an equilibrium is reached, exactly as much bromide appearing in the 
urine as is absorbed from the stomach. The excretion continues after 
the treatment is discontinued, and the drug is found in the urine for 
one or two months afterwards. When the body is thus saturated with 
bromides, some of the chloride combinations are replaced by them ; 
for example, Nencki found that the acid secreted by the stomach might 
contain more hydrobromic than hydrochloric acid. The substitution 
of bromide for chloride may be the cause of some of the symptoms of 
bromism ; one consequence is that the chlorides released from their 
combinations, are excreted in much larger quantity than usual in the 
urine. The nitrogenous metabolism does not seem to be affected, but 
in some cases a considerably smaller amount of phosphates appears 
in the urine. This has been supposed to be related to the action of 
bromides in lessening the mental activity, but is not by any means a 
constant effect. 

The bromides seem to be distributed in the body very much in the 
same proportion as the chlorides, being most largely found in the 
blood serum, while the brain and spinal cord contain them in com- 
paratively small proportion. 

The bromides are excreted mainly in the urine, but traces occur 
in the perspiration and milk, and some cases of bromism in children 



508 INORGANIC SALTS, ACIDS AND BASKS. 

have been recorded as due to their absorbing the bromide thus ex- 
creted by the nurse. In chronic poisoning the breath very often has 
a disagreeable odor, which has been attributed to bromine or some of 
its volatile organic compounds being excreted by the lungs, but noth- 
ing is known with certainty regarding it. Bromine has also been 
found in the hair after the prolonged use of bromides, and is supposed 
to exist in organic combinations here. The hydrobromic acid secreted 
into the stomach in bromism is probably all reabsorbed in the intestine. 

Bromide of Sodium differs from bromide of potassium chiefly in the 
absence of any changes in the heart or in the muscles exposed to its 
solution. The central nervous system also seems somewhat less de- 
pressed, because the potassium in itself has some effect, while the 
sodium ion is indifferent. 

Bromide of Ammonium owes most of its action to the bromide ion, 
unless when it is given in large quantities, when, according to several 
observers, the convulsive action characteristic of ammonium is devel- 
oped in animals. Smaller doses are followed by lethargy and weak- 
ness in animals, and in man the effects are practically identical with 
those of sodium bromide. 

Lithium Bromide has not been so largely used as the others, though 
it is said to be more depressant than bromide of potassium. 

Hydrobromic Acid possesses the characteristic bromide action after 
absorption, but has the local action of an acid and is consequently 
more irritant than the other members of the series. 

Strontium and Calcium Bromides seem to resemble the others in their 
general action and are said to disturb the digestion less. At the same 
time calcium and strontium salts are generally absorbed more slowly 
by the intestine than those of the alkalies. 

Preparations. 

Potassii Bromidum (U. S. P., B. P.) (KBr), 1-4 G. (15-60 grs.). 

Sodii Bromidum (U. S. P., B. P.) (NaBr), 1-4 G. (15-60 grs.). 

Ammonii Bromidum (U. S. P., B. P.) (NH 4 Br), 1-2 G. (15-30 grs.). 

Lithii Bromidum (U. S. P.) (LiBr), 1-2 G. (15-30 grs.). 

Calcii Bromidum (IT. S. P.) (CaBr 2 ), 2-4 G. (30-60 grs.). 

Strontii Bromidum (U. S. P.) (SrBr 2 ), 2-4 G. (30-60 grs.). 

Acidum Hydrobromicum Dilutum (U. S. P., B. P.) contains comparatively 
little bromide, as it is only a 10 per cent, solution in w r ater, so that a gramme 
of bromide of potash contains as much bromine as about 7 grammes of the 
dilute acid. 6-12 c.c. (*-3 fl. drs.) (B. P., 15-60 mins.). 

The bromides are all colorless crystalline bodies without odor l5ut with a 
saline, bitter taste, and are very soluble in water They are almost always 
prescribed in solution and ought to be taken diluted with a considerable 
amount of water in order to avoid the irritant action on the stomach. The 
prescription may be flavored with syrup and w T ith some of the volatile oil 
preparations. The large doses of the bromides render their hypodermic in- 
jection inadmissible, as concentrated solutions provoke pain and irritation in 
the subcutaneous tissues. 

A number of other bromide combinations are used in therapeutics, such as 
the hydrobromate of quinine, but here the bromide ion is present in very 
small' quantity compared with the alkaloid, and in the doses used in ther- 
apeutics has no appreciable effect. In monobromated camphor the bro- 



BROMIDES. 509 

mine is present in a different form and no bromide ion is liberated, so that 
the action of the metallic bromides cannot be compared with it. As a 
matter of fact, the bromine in this compound seems to have little or no 
effect. 

Therapeutic Uses. — The bromides are used chiefly in the treatment 
of epilepsy, in which they cannot be replaced by any other drug, and 
the prognosis of which has been entirely changed since their introduc- 
tion. In a few cases the bromide treatment is said to cure epilepsy — 
the attacks do not return after the treatment is stopped — but this is 
exceedingly rare ; in others the bromides have no effect, but in the 
great majority of cases (90-95 per cent.) the number of attacks is 
much smaller, or the patient may be entirely free from them as long as 
the treatment is persevered with, although they return as soon as it is 
given up. Very often no improvement is observed during the first 
few days, until the tissues have become saturated with bromide, but in 
other cases the spasms disappear immediately. The bromide of potas- 
sium is more commonly used than the others, and the general impres- 
sion is that it is more efficient and more certain in its effects, but some 
physicians prefer the bromide of ammonium or of lithium, and others 
still prefer a mixture of two bromides. In severe eases it is some- 
times found that the bromide action is strengthened by the addition of 
cannabis indica, opium or chloral, although the last two are to be used 
with caution. In the treatment of epilepsy it is well to begin with 
small doses and to increase them up to 10 G. per day, or until the de- 
sired effect is attained, or some complication, such as widespread skin 
affections, precludes their further use. 

The acne is very often a troublesome accompaniment of the bromide 
action, and in fact may prevent the use of this valuable drug in other- 
wise suitable cases. It may often be prevented by scrupulous clean- 
liness of the skin and frequently yields to treatment with small doses 
of arsenic. 

The bromides are not so effective in other affections of the central 
nervous system, although some success has attended their use in chorea, 
in the convulsions of children, and in some forms of hysteria. They 
have also been used in tetanus and in strychnine poisoning, but are 
inferior to other remedies such as chloral. Neuralgia is sometimes 
improved by bromide treatment, especially when it arises from worry, 
anxiety, or overwork. 

As soporifics, bromides often fail entirely, or induce such depression 
and confusion subsequently as to preclude their use. In sleeplessness 
from anxiety, they are often valuable, however, and it is found that 
the dose of chloral may be considerably lessened, if it is prescribed 
along with bromides. In sleeplessness from pain, bromide is of little 
or no value. 

Bromides have been used with good results in sea-sickness, in the 
sickness of pregnancy, and, it is said, in whooping-cough. Bromide 
of potash was formerly given internally to lessen the reflex movements 
of the throat and thus to permit of laryngoscopic manipulations, and 



510 INORGANIC SALTS, ACIDS AND BASKS. 

it was also applied locally to the throat for this purpose. It has now 
been superseded by the local use of cocaine. 

The Bibliography 

of potassium bromide, up to 1877, is given fully by 

Krosz. Arch. f. exp. Path. u. Pharm., vi., p. 1. See also 

Albertoni. Ibid., xv., p. 248. 

Loewald. Kraepelin's Psycholog. Arb., i., p. 489. 

Ach. Ibid., iii., p. 203. 

Wiersma. Ztsch. f. Psych, u. Phys. d. Sinnesorgane, xxviii., p. 179. 

Nencki u. Schoumow-Simanoivsky. Arch. f. exp. Path. u. Pharm., xxxiv., p. 313. 

Laudenheimer. Keurolog. Centralbl., 1897, p. 538. 

Bistroff. Arch. f. Anat. u. Phys., 1868, p. 721. (Ammonium bromide.) 

Amory. Bromide of Potassium and Bromide of Ammonium, Boston, 1872. 

Weir Mitchell. American Journ. of Med. Sciences, lx., p. 440. (Lithium bromide. ) 

Reichert. Boston Med. and Surg. Journ., civ., p. 505. (Hydrobromic acid.) 

Rosenthal. Ztschr. f. phys. Chem., xxii., p. 227. 

V. IODIDES. 

Although the iodides have been more largely used in medicine than 
any of the other salts of the alkalies, their mode of action is still 
wrapped in obscurity. This is due to the unsatisfactory state of the 
pathology of the diseases in which they are used, to the fact that the 
attention of investigators has been drawn to the symptoms of poison- 
ing rather than to the therapeutic action, and also to the fact that the 
effects seem to vary very considerably not only in different individuals, 
but also in the same person at different times. 

Symptoms. — Large quantities of the iodides cause irritation of the 
stomach from their salt-action, and induce nausea and vomiting, more 
rarely diarrhoea ; but these symptoms are quite distinct from those 
known as Iodism, which may arise from comparatively small quanti- 
ties, and which are most commonly seen when the remedy has been 
administered repeatedly. 

The commonest symptom of iodism is catarrh of the Respiratory- 
Passages, more especially of the nose, which betrays itself in some 
swelling and discomfort in the nasal mucous membrane, in a profuse 
watery secretion, and in sneezing. The catarrh spreads upwards to 
the conjunctiva, which often becomes swollen and congested, and to 
the frontal sinuses, where it induces a feeling of dulness or violent 
headache ; it also progresses downwards to the tonsils, which become 
swollen and inflamed in some cases. Still lower it occasionally causes 
some swelling and oedema or small ulcers in the larynx, and has thus 
caused dyspnoea, which has necessitated tracheotomy, or very rarely 
has proved fatal. Bronchitis has also been observed in man, with a 
profuse watery secretion, and in animals oedema of the lungs and 
pleuritic effusion have been produced by the ^injection of iodides. 
Even small quantities injected intravenously increase the mucus se- 
creted by the bronchi. 

In the Mouth iodism is often betrayed by swelling and irritation of the 
throat and tonsils, and by salivation, rarely by swelling of the salivary 
glands. The stomach is seldom affected, the appetite generally remain- 



IODIDES. 511 

ing good, but in some persons iodides induce nausea and gastric dis- 
comfort. 

Skin Eruptions of different forms are also common results of the 
administration of iodides, but are less liable to occur in the beginning 
of the treatment than the catarrh of the respiratory passages. These 
eruptions may simulate almost all known skin diseases, but the most 
common forms are erythematous patches, or papular eruptions which 
may pass into pustules or into larger inflamed areas. Eczema, bullae, 
pemphigus, and purpura arise less frequently from the use of iodides. 
In some cases, a more or less defined area of oedema has been observed 
in the face. 

The Secretion of Urine is generally increased by the administration 
of iodides, as of other salts of the alkalies, though they seem to have 
no specific action on the kidneys. In rare cases albuminuria has been 
observed, and some irritation of the bladder, urethra, and vagina is 
said to have been induced by iodide treatment, but these statements 
require confirmation. 

Not infrequently the Pulse is accelerated, though this is not constant. 

The Central Nervous System seldom seems to be affected by the treat- 
ment. In rare cases paralysis, tremors and various disorders of sen- 
sation, such as localized anaesthesia or neuralgic pains, have been 
recorded, but it seems open to question whether these were in all cases 
the direct result of the medication. 

A slight rise of Temperature has also occurred, often apparently- from 
the skin affections or the catarrh ; in some doubtful cases apparently 
without any such cause. 

Loss of Weight has been noted a number of times both in man and 
animals. This is seen more frequently in thyroid disease (goitre) than 
elsewhere, and in these cases the goitre is often reduced in size. It is 
still disputed whether the prolonged use of iodides lessens the size of 
the testicles and of the mammary glands. 

In some rare cases of very prolonged iodism, a Cachexia has been 
observed, with great loss of flesh, weakness, depression, mental con- 
fusion, restlessness and aberrations of sensation. These did not disap- 
pear at once when the treatment was discontinued, as the ordinary 
symptoms of iodism do. 

In many instances, small doses of iodide may be given repeatedly 
without any noticeable disturbance, but in others, the smallest quantity 
(0.2 G.) induces severe poisoning. Some authorities consider that 
these small doses are more liable to cause iodism than larger ones, but 
this may be doubted, as the action of the drug is so capricious, that 
the statistics of different observers show great discrepancies, even 
when approximately the same dose has been given. Thus, Haslund, 
treating patients with at first 3 G. (45 grs.) and then 5 G. (80 grs.) 
daily, observed iodism in only 12 per cent, of his cases during the first 
few days, while others have found iodism induced in 60 per cent, of 
their cases after a single dose of 3 G. An attempt has been made to 
explain these discrepancies by supposing that iodism is only produced 



512 INORGANIC SALTS, ACIDS AND BASES. 

by impure iodides, but this is not correct, for it has been observed in 
numerous cases in which the drug was absolutely pure. Among other 
conditions which favor the onset of symptoms, is a slow excretion of 
the iodide such as is observed in some forms of renal irritation. 
Children seem less liable to suffer from the iodides than adults. The 
dose administered has, of course, some relation to the onset of symp- 
toms ; thus, very large doses are more likely to induce them than very 
small ones, but it seems that a tolerance is soon established in some 
cases, for after iodism has been induced, and the daily dose lessened 
accordingly, it is sometimes found that it may be gradually increased 
until a quantity considerably greater than that originally given may 
be taken with impunity. In other instances, a definite quantity may 
be given for a long time without inducing symptoms, but these may sud- 
denly set in without any apparent change in the treatment and without 
any appreciable cause. Very often it is found that the symptoms dis- 
appear when the treatment is continued, and recovery invariably sets 
in when the drug is abandoned. The iodides all induce iodism, the 
symptoms being apparently unaffected by the basic ion, but the iodide 
of ammonium is said to be more liable to induce them than the others, 
owing to the iodine being freed from it more easily. The symptoms 
are seldom dangerous, but a few cases are recorded in which oedema 
of the larynx resulted and proved fatal, and in others death was attri- 
buted to the iodides, but the exact cause was not ascertained. 

The iodides are not Absorbed from watery solutions applied to the 
skin, but are rapidly taken up by all the mucous membranes. When 
given by the mouth they are absorbed unchanged by the stomach and 
intestine, and appear in the secretions within a few minutes. The 
greater part of the iodide is Excreted in the urine, in which it ap- 
pears as salts. Some escapes by the salivary glands, however, and small 
quantities are excreted by the stomach as hydriodic acid and some- 
times as free iodine ; iodide has also been found in the tears, per- 
spiration, milk, sebum, and in the secretion of the nasal mucous 
membranes. No iodine can be detected in the breath of animals 
poisoned with iodides. After treatment with iodide of potash, iodine 
has been detected in the hair, milk, muscles and heart in organic 
combination. Iodides are much more rapidly excreted than bromides, 
for 65—80 per cent, of the iodide appears in the urine within 24 hours 
after its administration, and no iodide reaction is obtained from either 
urine or gastric juice a week after the treatment has ceased. Ac- 
cording to an old statement of Claude Bernard, the saliva contains 
traces of iodine for weeks after the excretion through the kidneys has 
stopped. It has been stated that iodide fails to pass into the serous 
cavities in inflammatory transudates, but this seems to be incorrect, 
although the starch test often fails here from the presence of proteids. 

The greater part of the iodide administered therefore passes 
through the tissues and is excreted in the urine in the form of salts. 
If iodide of potassium be given, as is generally the case, some inter- 
change between it and the salts of the tissues takes place and iodide 



IODIDES. 513 

of sodium, chloride of potash and several other salts are formed, and 
all of these are excreted in the urine. Some of the iodide undergoes 
decomposition in the body, however, and the free iodine thus formed 
is believed to be the cause of the symptoms of iodism. This decompo- 
sition of iodides in the body was at first rather inferred from the sim- 
ilarity of the symptoms with those induced by iodine preparations, than 
from the actual demonstration of the presence of iodine in the tissues. 
The ordinary iodine tests fail in albuminous solutions, because it ap- 
pears to exist in a loose combination with the proteids, but free iodine 
has been shown to be excreted into the stomach, and an organic com- 
pound of iodine exists in the hair and in various internal organs after 
iodide treatment. The successful treatment of goitre with iodide of 
potassium is also a strong argument in favor of the presence of free 
iodine, and the iodothyrin of the thyroid gland has been shown to be 
increased by potassic iodide. If it be correct that the iodine reaction 
can be obtained from the saliva for weeks after the treatment has been 
stopped, this would also suggest that some other combination than the 
simple salts is formed in the body, for it is unlikely that such soluble 
bodies as the ordinary iodides could circulate for this length of time 
and escape the excretory organs. When iodine is thus liberated in the 
body, it does not circulate as such, but at once combines with the pro- 
teids. 

The formation of free iodine from iodides (which is, of course, quite dis- 
tinct from their dissociation into potassium and iodide ions) has been ex- 
plained by several theories. The first of these assumed that the iodide was 
decomposed by the carbonic acid of the blood, forming hydriodic acid, and 
that this was subsequently oxidized in the blood to free iodine. Binz sup- 
posed that the decomposition occurred rather in the protoplasm of the tis- 
sues, and supported his statement by an experiment in which an iodide solu- 
tion was saturated with carbonic acid and had plant protoplasm added to it, 
after which it gave the ordinary iodine reaction with starch. The objection 
has been raised that this experiment succeeds only when dying protoplasm 
is used, and another theory has been proposed, namely, that the oxidation 
is carried on, not by the protoplasm itself, but by some unstable substances 
which are excreted by living matter, and which therefore occur on the mucous 
membranes, iu the saliva . and elsewhere. These bodies are in themselves 
reducing agents, but in the presence of air, as in the respiratory passages, 
their oxidation is accompanied by the liberation of " active oxygen " which 
in turn oxidizes the iodides. Another explanation which has beeu given for 
the occurrence of free iodine is the action of nitrites, which decompose iodide 
of potassium in the preseuce of acids. If these nitrites be excreted in the 
saliva therefore, as is often the case, and there meet with iodides in an acid 
medium, free iodine is formed and some irritation arises. It has been stated 
recently that iodism is very readily elicited in patients whose saliva contains 
much sulphocyanide, and that the occurrence of this body in the secretions 
of the respiratory tract is responsible for the manifestations of irritation in- 
duced by iodides. Binz has found that some microbes are capable of setting 
iodine free from acid solutions of the iodides. 

Iodine is supposed to be set free along the mucous membrane of the 

respiratory passages and in the skin ; and in this way the coryza of the 

former, and the eruptions on the latter are explained. It must be noted 

that free iodine has not yet been clearly demonstrated in either of these 

33 



514 INORGANIC SALTS, ACIDS AND BASES. 

surfaces, and that the theory has been formulated only to explain the 
symptoms of iodism. Iodides have been found in the nasal secretion, 
saliva, and perspiration, but no free iodine. Some of the other symp- 
toms of iodism are probably due to action on the thyroid gland ; thus 
the acceleration of the heart observed in some cases, the loss of flesh 
resulting from their prolonged use in others, and the reduction in the 
size of goitres may all be explained in this way. (See Thyroid Extract.) 

The central nervous system and the circulation scarcely seem to be affected 
by iodides. Very large quantities of potassic iodide injected into a vein are 
found to weaken and paralyze the heart in animals, but do not seem to be 
more poisonous than other potassium salts, and depression of the central 
nervous system may also be elicited in the same way by the potassium 
action. Barbera states that very large quantities of iodides paralyze the 
depressor nerve terminations in the medulla oblongata and weaken the pe- 
ripheral inhibitory mechanism of the heart, while Hunt found the accelera- 
tor fibres less easily fatigued after iodide. The metabolism of the body 
seems little affected by iodides in most cases, but a further examination of 
the excretions of patients who lose weight under the treatment is desirable. 
The action of the iodides in therapeutics has been ascribed by some authors 
to their rendering the movement of the leucocytes (diapedesis) more active, 
but no satisfactory evidence has been adduced in support of this. Solutions 
of iodide of sodium are found to be more poisonous to muscle, cilia and 
unicellular organisms exposed to them than are similar solutions of the 
chloride or bromide, so that the iodide ion appears to be more fatal to 
protoplasm than the bromide and chloride ion, while it is less poisonous than 
the fluoride. In the frog stiffness and awkwardness in the movements are 
elicited by comparatively small doses of iodide of sodium and these symp- 
toms have been shown to be due to rigor mortis occurring in the muscles. 

Preparations. 

Potassii Iodidum (U. S. P., B. P.) (KI), 0.1-1.3 G. (2-20 grs.). 

Unguentum Potassii Iodidi (U. S. P., B. P.). 

Linimentum Potassii Iodidi cum Sapone (B. P.). 

Sodii Iodidum (U. S. P., B. P.) (Nal), 0.1-1.3 G. (2-20 grs.). 

Ammonii Iodidum (U. S. P.) (NH 4 I), 0.1-1 G. (2-15 grs.). 

Strontii Iodidum (U. S. P.) (Srl 2 ), 0.3-1 G. (5-15 grs.). 

Syrupus Acidi Hydriodici (U. S. P.), a syrup containing about 1 per cent, 
by weight of hydriodic acid. 4 c.c. (1 fl. dr.). 

The iodides form colorless crystals when pure, a yellowish tint indicating 
the presence of free iodine. They are very soluble in water, less so in alco- 
hol, and are always prescribed in watery solutions, and often along with 
carbonates of soda or potash, in order to prevent decomposition as far as 
possible. The iodide of potash is the one most frequently used and is less 
liable to contain free iodine than the others, but iodide of soda is preferred 
by some ; the dose often has to be much increased beyond that given above. 
The iodide of ammonium is said to be more liable to cause skin eruptions 
and disturbance of the digestion than the others. Some iodide effects may 
also be obtained by the use of iodide of lead or mercury, but here they 
are complicated by the action of the metal, and these will be discussed 
along with the other salts of lead and mercury. The external application 
of iodides, as in the ointment or liniment of potassic iodide, is not attended 
by any effect local or general. 

Therapeutic Uses. — The iodides are used very extensively in the 
treatment of tertiary syphilis, in which they have proved invaluable. 






IODIDES. 515 

They have also been administered in the earlier stages of the disease, 
but have proved to be of little service here. In syphilitic bone disease 
and ulcers, and in the gummata of the brain and other internal organs, 
however, a remarkable improvement very often occurs after the iodide 
treatment has been adopted. The iodide of potassium or of sodium is 
almost invariably used, and is given in as large doses as the patient can 
bear, often up to 5 G. (75 grs.) daily. In the beginning of the tertiary 
manifestations, the iodide is often prescribed along with mercury, and 
this combination is found more efficient than the iodide alone. No 
explanation of the action of the iodides in syphilis has been given, 
although it is surmised that they may act as a specific poison (anti- 
septic) to the unknown cause of the disease. It is suggested by some 
writers (Binz) that the iodine is set free in the gumma or in its neigh- 
borhood, as in the saliva and on the skin, but this is pure speculation, 
unfounded on any basis of fact. 

In many diseases which are not directly attributable to syphilis, 
but in which there is a history of syphilis, iodides are of value ; thus, 
neuralgia and other nervous disturbances are often relieved by them 
in persons of a syphilitic taint, and in fact, improvement is often ob- 
served in the most diverse conditions in persons who have formerly 
suffered from this complaint. 

Another series of symptoms or of diseases which is often treated 
with iodides, is rheumatism in its various manifestations. The treat- 
ment is of little value in acute rheumatism, and in fact, often fails in 
the chronic disease, but is occasionally attended with improvement, 
although the exact conditions in which this occurs are still unknown. 

The iodides have long enjoyed some reputation in the treatment of 
goitre, but the thyroid extract has proved much superior to them and 
promises to supplant them entirely, as their effects are due to their 
action on the thyroid secretion. The same may be said regarding their 
use in obesity, which was found to be successful in some cases, pre- 
sumably of thyroid insufficiency. In normal persons and animals it 
is often found that iodides rather tend to increase than to decrease the 
weight. 

Some skin eruptions have been found to be benefited by the iodide 
treatment even when no suspicion of syphilis could be entertained. 
(Compare thyroid extract.) 

The success attending the treatment of goitre with iodides seems to 
have been the basis of their use in cases of enlarged lymphatic glands, 
scrofula, and lupus, but here the results are very doubtful, although 
some authorities allege that the iodide treatment is of value. There is 
a general consensus of opinion that the old treatment of malignant 
tumors, such as cancer and sarcoma, with iodides is hopeless. 

These salts are sometimes credited with promoting the absorption of 
serous effusions, but here again it seems doubtful if their reputation is 
merited. The same may be said of their use to aid in the removal of 
hypertrophy of connective tissue in the body, as in the various forms 
of sclerosis and cirrhosis although the iodides are still very widely 



516 INORGANIC SALTS, ACIDS AND BASES. 

used in arteriosclerosis. Their effect in removing the syphilitic 
gumma was evidently the origin of their use here, but while the resolu- 
tion of gummata under the iodides is beyond question, the evidence of 
improvement in arteriosclerosis in patients free from syphilitic taint is 
not so decided, and in fact the use of iodides in this condition is con- 
demned by many authorities. Heinz has attempted to find a scientific 
basis for the treatment of exudates and connective tissue hypertrophy 
with iodides, and suggests that the vessel walls are rendered more per- 
meable and the leucocytes more active by these salts, but fails to bring 
any convincing evidence for either hypothesis. 

At one time aneurism was treated with large doses of iodide, and 
improvement was undoubtedly observed in some cases, in which there 
was probably a syphilitic taint ; but there seems no reason to suppose 
that the iodides have any special action on the vessels apart from their 
antisyphilitic action. 

Iodides are often prescribed along with other remedies in expecto- 
rant mixtures, the object being to render the bronchial mucus more 
watery and less tenacious, and thus to facilitate its removal. In some 
cases of asthma they have been found of value, perhaps from the 
same action. 

Iodide of potassium is generally prescribed in chronic poisoning from 
lead or mercury, and is believed to hasten the elimination of these 
metals, although it has not been shown that it is of more value here 
than other salts such as the chlorides and bromides. The belief in the 
efficacy of the iodides in mercury poisoning has suggested that they 
act in tertiary syphilis only by aiding in the elimination of the mer- 
cury stored in the tissues from the treatment of the earlier stages, but 
this is incorrect, for the iodides are of value in cases of tertiary syphi- 
lis in which mercury has not been previously used. 

Finally, iodide of potassium is sometimes added to other drugs in 
cases of malingering, or in which it is suspected that the patient is not 
taking the remedy as directed. If the iodide is swallowed it can be 
detected in the urine by the addition of a few drops of chlorine water 
and of starch solution, which assumes the well-known blue color. 

Iodides have to be used with care in cases of pulmonary phthisis, 
in which they often increase the cough and expectoration, and in some 
cases, it is alleged, cause haemoptysis. Children have sometimes been 
found to suffer with iodism from being nursed by a person under 
iodide treatment. 

Iodism very often proves a disagreeable accompaniment of the 
treatment, and is sometimes so severe as to preclude the use of the 
salts, so that many attempts have been made to discover some expedi- 
ent by which these symptoms may be avoided. Ehrlich proposed the 
use of sulfanilic acid in order to decompose the nitrites, by which he 
supposed that the iodide was decomposed and the iodine set free in the 
respiratory passages ; but Lewin has shown that sulfanilic acid does 
not combine with nitrites in the body, and the clinical results of this 
treatment have not been very encouraging. Another method of pre- 






IODINE. 517 

venting iodism is the prescription of bicarbonate of soda along with 
the iodide, with the object of rendering the surface of the mucous 
membranes more alkaline, and thus preventing the action of the ni- 
trites on the iodides. This seems, like the use of sulfanilic acid, suc- 
cessful in a certain number of cases, but not in all. 

The cutaneous eruptions are said to be less liable to occur when the 
skin is kept scrupulously clean by frequent bathing, 

Bibliography. 

Blum. Munch, med. Woch., 1898, pp. 231 and 267. 
Rose. Virchow's Arch., xxxv., p. 12. 

Binz. Ibid., lxii., p. 124. Arch. f. exp. Path. u. Pharm., viii., p. 320; xiii., p. 
139 ; xxxiv., p. 185. 

Buchheim. Arch. f. exp. Path. u. Pharm., iii., p. 104. 

Boehm u. Berg. Ibid., v., p. 329. 

Hogyes. Ibid., x., p. 250. 

Rozsahegyi. Hofniann-Schwalbe's Jahresber., 1879, p. 198. 

Adamkiewicz. Char. Annal., iii., p. 381. 

Bogolepoff. Virchow-Hirsch Jahresber., 1876, i., p. 402. 

Ehrlich. Char. Annal., x., p. 129. 

Groenouw. Therap. Monatsh., 1890, p. 105. 

R-ihmann u. Malachowski. Therap. Monats., 1889, p. 301. 

Kulz. Zeitschr. f. Biologie, N. F., v., p. 460. 

Nencki u. Schoumow-Simanowski. Arch. f. exp. Path. u. Pharm., xxxiv., p. 313. 

Ehlers. Monatsh. f. pract. Dermatol., 1889, i.. p. 428. 

Prevost u. Biaet. Therap. Monatsh., 1890, p. 640. 

Howald. Zts. f. physiolog. Chem., xxiii., p. 209. 

Annuschat. Arch. f. exp. Path. u. Pharm., x., p. 261. 

Stockman and Charteris. Journ. of Physiol. , xxvi., p. 277. 

Heinz. Virchow's Arch., civ., p. 44. 

Gumprecht. Verhandl. d. Congress, f. inn. Med., xix., p. 260. 

VI. IODINE. 

Iodine possesses a local irritant action similar to, though less intense 
than that of chlorine and bromine. It is much less volatile, and there- 
fore comes into contact with the tissues more slowly than these, but 
the chemical change is analogous, and iodides and proteid compounds 
result. 1 

Action. — When applied to the Skin, it dyes it a yellow-brown or 
dark brown color, and acts as an irritant, producing a sensation of heat 
and itching. In very concentrated solution or in the solid form, it 
may cause blistering or even corrosion, but it acts much more slowly 
than most other irritants, and at the same time the irritation is more 
prolonged. It penetrates into the deeper layers of the skin, and small 
quantities are absorbed. 

The Mucous Membranes are more strongly affected by contact with 
it ; thus when its vapor is inhaled for some time, smarting, swelling 
and increased secretion is caused in the nasal mucous membrane, 
conjunctiva, throat and lower respiratory passages, resembling exactly 
the symptoms known as iodism. In the stomach small quantities may 

*It therefore differs entirely from the iodides and the other salts, as far as its local 
action is concerned, but there are so many points of connection between the halogen 
and the salts that it has been found convenient to insert it here. The same remark 
holds good for the next series (Iodoform). 



518 INORGANIC SALTS, ACIDS AND BASES. 

cause slight irritation and improved appetite, but as a general rule 
nausea, discomfort and vomiting follow its administration in any save 
the most minute doses, and occasionally diarrhoea has been observed 
after it from irritation of the bowel. In cases of poisoning, the irri- 
tation of the alimentary canal may prove fatal by inducing collapse 
and failure of the heart and respiration, and iodine may be recognized 
in the vomited matter and in the stools. 

Solutions of iodine Injected Subcutaneously or into tumors or cysts, 
a common method of treatment formerly, cause intense pain and irri- 
tation which may induce collapse and which have been followed in 
some instances by suppuration and gangrene. 

Iodine is Absorbed in the form of iodides, and perhaps in a combi- 
nation with proteids. The ordinary iodalbuminate obtained by adding 
iodine to albumin, is a very loose compound, and is easily decomposed 
by dialysis, or by heating it to the coagulation point of the albumin, 
when the iodine is obtained free or in combination with alkalies. Sev- 
eral stronger and more definite compounds have been formed recently, 
and it is not impossible that the iodalbuminate formed in the process 
of absorption is of a similar nature. In combination with albumin, 
iodine fails to give the starch reaction. Its Fate in the Body is pre- 
cisely similar to that of the iodides — it is excreted in the form of 
iodides, chiefly by the kidneys, to a less extent in the saliva, perspira- 
tion, milk, and secretions of the respiratory passages. It also occurs 
in the stomach, into which it appears to be excreted as hydriodic 
acid ; free iodine has been detected here in both man and animals, 
and is probably formed by the decomposition of the acid. In the 
normal organism iodine is contained in considerable quantity in the 
thyroid gland in the form of an organic compound, iodothyrin, and in 
many cases the administration of iodine leads to an increase in the for- 
mation of this substance, perhaps by actually stimulating the secretory 
cells of the thyroid, but more probably by affording them a larger 
amount of a necessary constituent of their secretion than is contained 
in ordinary food. 

Small quantities of iodine may be given internally to many persons 
without eliciting any symptoms except those which are clearly due to 
the local action. Repeated doses, however, sometimes cause symp- 
toms resembling those observed after iodides (Iodism), although these 
have been much less often induced by iodine, which is comparatively 
seldom administered internally. Skin affections seem to be extremely 
rare, but that a similar action on the skin may be induced by iodine 
and iodides, is shown by the application of iodine to the skin being 
often followed by eruptions, which are not confined to the point of 
application but spread over the skin and assume the form of diffuse 
erysipelatoid rashes, papules, or erythemata. Fever is said to occur 
occasionally, especially in goitrous patients, and a loss of flesh has been 
observed with shrinking in size of the thyroid gland and, it is said, of 
the mammae and testicles. The pulse is often accelerated to a very 
considerable extent, and in cases of goitre treated for some time by the 



IODINE. 519 

internal and local administration of iodine, a curious nervous condition 
was often observed formerly. The patients became restless, anxious 
and irritable, and suffered from sleeplessness and often from tremor, 
which sometimes simulated chorea. All of these symptoms except the 
skiu eruptions and the atrophy of the mamma and testis, the occurrence 
of which under iodine requires confirmation, are induced by large quanti- 
ties of thyroid extract also, and would seem to be due to the excessive 
production of iodothyrin. 

Irritation of the respiratory tract is seen less often after iodine than 
after the iodides, but oedema of the larynx has been observed, and in 
rare cases cough and the expectoration of a watery secretion tinged 
with blood. 

Anuria and albuminuria have occurred in a few instances. 

The symptoms induced by iodine after absorption thus resemble in 
general features those following the use of the iodides, but while the 
latter tend to cause irritation of the skin and respiratory tract, pre- 
sumably through liberating iodine here, the chief effects of iodine after 
absorption are due to its action on the thyroid gland, the effects on the 
skin and mucous membranes being less prominent. 

The effects of iodine on the Metabolism are still a matter of dispute, 
some authors finding no alteration, while others state that the excretion 
of urea is increased. They probably differ in different individuals 
according to the condition of the thyroid gland. 

Injected into the veins of animals, iodine causes oedema of the lungs, 
which v. Zeissl considers to be due in part to changes in the left ven- 
tricle, in part a contraction of the pulmonary arterioles. 

The muscles of the frog are thrown into a state of rigor by iodine in 
the same way as by the iodides. 

Some Cases of Poisoning from the injection of large quantities of 
iodine into cysts have been recorded. In Rose's well-known case, the 
chief symptoms were thirst, constant vomiting, the vomited matter 
containing iodine, cyanosis and coldness of the skin, a small, weak 
pulse, anuria and skin eruptions after a few days ; and death occurred 
on the tenth day. In such cases of poisoning in man the mucous 
membrane of the stomach and intestine has been found swollen and 
loosened, and in animals fatty degeneration of the liver, heart and 
kidney has been described. 

Iodine is said to dissolve the red blood corpuscles when it is brought 
in contact with them outside the body, and to form a combination with 
hemoglobin. 

Preparations. 

Iodum (IT. S. P., B. P.), iodine, a heavy, friable, bluish -black mass, with 
a characteristic odor and acrid taste, insoluble in water, soluble in alcohol 
and in solutions of the iodides of the alkalies. Iodine itself is not used in 
therapeutics. The solutions are of a brown color. 

Tinctura Iodi (U. S. P.), 7 per cent., 0.1-0.4 c.c. (2-8 mins.). 

Tinctura Iodi (B. P.), 2.} per cent., 2-5 mins. 

Liquor Iodi Compositus (U. S. P.), Lugol's Solution, contains 5 per cent, 
dissolved in 10 per cent, potassium iodide solution. 0.2-0.8 c.c. (3-12 mins.). 



520 INORGANIC SALTS, ACIDS AND BASES. 

Unguentum Iodi (U. 8. P., B. P.), 4 per cent. 

Liquor Iodi Fortis (B. P.), Iodine Liniment, about 14 per cent. 

Sulphuris lodidum (U. S. P., B. P.) is a mixture of iodine and sulphur, 
part of which may be in chemical combination. It resembles iodine in its 
action on the skin. 

Unguentum Sulphuris Iodidi (B. P.). 

The compound solution of iodine is the preparation best fitted for internal 
use, although the tincture is also employed. Both should be given after 
meals and as far as possible diluted with demulcent preparations, in order 
to avoid irritation of the stomach. 

For injection into cysts or tumors the compound liquid is also the best 
preparation, as it is less irritant than the tincture. 

The tincture, ointment, the strong solution (B. P.) and the sulphur iodide 
preparation may be used for external application. 

Therapeutic Uses. — Iodine has been used internally in a variety of 
chronic conditions such as syphilis and goitre, and in tubercular dis- 
ease of the glands, bones and other organs, but it has been almost 
entirely superseded by the iodides, and in goitre by the thyroid prepara- 
tions. It was formerly applied in goitre by injection into the enlarged 
lobes of the gland, as well as being administered internally, and cer- 
tainly proved beneficial in many cases, though these are better treated 
now by the extracts of the gland. 

The internal use of iodine has undergone a revival quite recently, but in- 
stead of the older solutions, new preparations have been introduced such as 
the combinations with proteids (Eigon, Iodolen) or with fats {Iodipin), and 
the organic compounds of the iodoform series. Iodipin is decomposed by 
the pancreatic juice and iodides appear in the urine soon after this takes 
place. It has been used to indicate the activity of the gastric movements, 
as when these are abnormally slow the reaction in the urine appears later 
than in normal cases. 

It has also been applied locally by painting on the skin in a variety 
of chronic inflammatory processes, such as tubercular glands, pleuritic 
effusion, and tubercular or rheumatic joint disease. Its action here 
consists simply of a mild lasting irritation of the skin, which induces 
some congestion in the subcutaneous tissues and may thus aid in the 
absorption of exudates in them and may also influence the deeper lying 
tissues and organs in the same way as other irritants (see page 78). 
There is, however, nothing specific in its action, and it differs from the 
other skin irritants only in being milder in action and more enduring 
in its effects. It seems unlikely that the small quantity absorbed can 
have any appreciable action. Some benefit often follows from this 
use of iodine in chronic inflammations, but there is no question that it 
is very often applied where more active surgical measures are really 
required. 

Iodine has been very frequently injected into cysts in order to in- 
duce inflammation and adhesion of their walls, and thus to obliterate 
the cavity. Formerly ovarian cysts were very generally treated in 
this way, but a number of cases of poisoning arising from this treat- 
ment, and the progress of abdominal surgery have led to its being 
abandoned. Hydrocele is still very frequently treated with iodine in- 



IODOFORM. 521 

jection, and some cysts of the membranes of the spinal cord and brain 
are injected with it. It has been stated in this connection that these 
membranes react much less violently to iodine than the peritoneum 
and the lining membranes of the joints. Iodine has also been injected 
in dilute solution into the pleuritic cavity after the evacuation of 
empyema. 

Bibliography. 

See Iodides, Thyroid Extract. 

Liebrecht. Centralbl. f. Physiol., 1897, p. 835. 

Hofmeister. Ztschr. f. phys. Chem., xxiv., p. 159. 

Winternitz. Ibid., xxiv., p. 425. 

Levene. Amer. Journ. of Phys., ii., p. 15. 

VII. IODOFORM. 

A number of iodine compounds have been introduced into thera- 
peutics as applications to wounded surfaces. The most widely known 
of these is Iodoform (CHI 3 ), which corresponds in its chemical struc- 
ture to chloroform, and forms a yellow, crystalline, insoluble powder 
with an intensely disagreeable odor. It has been used very exten- 
sively in surgery, and has given rise to poisoning in a number of cases. 

Symptoms. — The symptoms of iodoform intoxication in man gener- 
ally set in with anxiety, general depression and discomfort. The pa- 
tient becomes sleepless and restless, complains of giddiness and head- 
ache and often of the taste and odor of iodoform in the mouth and 
nose. The pulse is generally greatly accelerated, and a rise of tem- 
perature is said to have occurred in some cases in which no septic 
poisoning could be found to account for it. The depression deepens 
into true melancholia accompanied by hallucinations, the patient often 
suffering from the illusion of persecution, which may induce him to 
attempt suicide. As a general rule this melancholia is followed by 
attacks of violent delirium and mania, lasting for hours or days, and 
in fatal cases, by collapse and death. In other cases the condition has 
passed into permanent insanity and dementia. A rarer result of the 
absorption of iodoform is deep sleep passing into stupor and collapse 
without any symptoms of cerebral excitement. 

In milder cases of poisoning the patient suffers only from the un- 
pleasant taste and odor, from headache and not infrequently from 
nausea and vomiting. 

In the dog and cat iodoform generally causes deep sleep and stupor, 
with lessened excitability of the spinal cord and of the motor areas of 
the brain. In the frog it paralyzes the central nervous system and the 
heart without eliciting any symptoms of excitement. No narcosis is 
observed in the rabbit even after fatal doses. 

The symptoms most characteristic of iodoform poisoning — those of 
delirium and mania — are evidently due to cerebral disturbance, but 
nothing is known as to the nature of the changes in the brain. No 
other poison elicits these symptoms in the same intensity and of equal 
duration, and no similar effects have been met with in animals. 



522 INORGANIC SALTS, ACIDS AND BASKS. 

Acceleration of the heart has been noted in many cases of poisoning. 
After prolonged administration albuminuria is often observed in ani- 
mals, and the thyroid secretion has been found to be increased to a 
very considerable extent by iodoform, as by other bodies which free 
iodine in the tissues. 

After fatal iodoform poisoning in man and animals, the liver, kidney, 
heart and muscles are generally found to have undergone fatty degen- 
eration. In addition, irritation of the gastric and intestinal mucous 
membrane has been observed, and the epithelial cells are often degen- 
erated. Ecchymoses occur beneath the endocardium, in the kidney 
and elsewhere, and congestion of the meninges is described. 

Absorption and Excretion. — Iodoform is readily decomposed in the 
presence of alkaline fluids and in proteid solutions, and some decom- 
position undoubtedly takes place in wounds ; the iodine liberated 
combines with the alkalies of the fluids to form iodides, for these have 
been shown to be present, and iodalbuminates are presumably formed in 
the same way as by free iodine. Some of the iodoform, however, is 
absorbed unchanged, for the nervous symptoms are not produced by 
iodine or iodides. After iodoform absorption, iodine has been shown 
to be present in the saliva, perspiration and bronchial secretion, as 
after the ingestion of iodine or iodides ; but it is chiefly excreted in 
the urine in the form of iodides. The tissues apparently retain it very 
tenaciously, for iodides have been found in the urine for more than a 
month after the administration of iodoform. Harnack has stated that 
in iodoform poisoning much of the iodine of the urine is in organic 
combination, but this has been denied by later writers. 

In considering the symptoms of iodoform intoxication, it must be 
recognized, therefore, that a very complex condition is present. Some 
iodoform circulates in the blood apparently unchanged and gives rise 
to the cerebral symptoms. Other symptoms are due to the presence 
of iodine and iodides, perhaps the former chiefly, in the blood and tis- 
sues, for Rummo observed in dogs the excessive secretion from the 
eyes, nose and bronchi, which is characteristic of iodism. Lastly, 
the acceleration of the heart and some other symptoms may be due to 
abnormal activity of the thyroid secretory cells. 

Poisoning with iodoform is much more liable to occur in adults than 
in children. Serious symptoms, especially mental symptoms, are often 
developed only after somewhat prolonged administration, but in renal 
disease the iodoform products are excreted more slowly than usual, and 
are liable to accumulate in the tissues, so that it is to be used with 
caution. 

Iodoform has no marked Local Action on the skin or mucous mem- 
branes. When applied to wounded surfaces it sometimes causes some 
irritation in the neighborhood and even exanthemata, but these are rare, 
and appear to occur only in persons predisposed to cutaneous disease. 
It seems to have some anaesthetic action, when applied in large quantity 
to wounded surfaces. Iodoform was at first applied to wounds in the 
belief that its Antiseptic properties were equal to or even exceeded 



IODOFORM. 523 

those of carbolic acid. It has been shown, however, that it possesses 
little or no influence on the cultures of most of the pathogenic mi- 
crobes, for the spores often develop as rapidly after having been sub- 
jected to iodoform as in the control cultures. It has therefore been 
suggested that while iodoform in itself possesses no antiseptic virtues, 
the iodine formed from it in the wound may retard the growth of sep- 
tic germs. And in regard to this point bacteriologists are not agreed, 
for while several investigations tend to show that microbes drawn from 
wounds under iodoform treatment are not retarded or weakened in their 
development, other experiments indicate that the virulence of some 
germs is reduced. Some of the advocates of the iodoform treatment 
therefore ascribe its results to this slight antiseptic action of the iodine, 
while others suppose that it diminishes the secretion of the wounded 
surface and thus affords a less suitable medium for the growth of the 
germs ; in this relation it may be mentioned that Binz found the emi- 
gration of the leucocytes from the blood vessels hindered by the local 
application of iodoform. Finally iodoform may retard the growth of 
microbes to some extent by forming a crust over the wounded surface, 
and mechanically preventing them from penetrating to it. 

The intensely disagreeable odor of iodoform and the considerable 
number of cases of poisoning noted under its use have led to the intro- 
duction of numerous substitutes in the last ten years. Some of these 
have been shown to be practically worthless and have been discarded, 
while the greater number are apparently used more or less widely, but 
accurate data as to their value cannot be obtained. None of them seem 
to be very poisonous, and in most of them the iodine of the molecule 
is not liberated in the wound or tissues. It is of course impossible to 
state how far they are capable of replacing iodoform, as long as their 
exact action in wounds is unknown. 

The first of these substitutes was iodol or tetraiodpyrrol (C 4 I 4 NH), which 
has no odor or taste, is insoluble in water, but is absorbed from mucous sur- 
faces and from wounds. It is decomposed in the tissues, and leads to the 
excretion of iodides in the urine, and in very large doses gives rise to symp- 
toms in animals resembling those produced by iodoform. The iodine of 
iodol is apparently less easily split off the molecule than that of iodoform, 
and it seems on the whole less liable to produce poisoning, but has been less 
used of late years than some of its rivals. Among the best known of these 
are aristol or dithymol-diiodide (C 6 H 2 CH 3 C 3 H 7 OI) 2 , and the sozoiodolates of 
potassium, sodium, mercury and zinc. Sozoiodolic acid is phenol-sulphonic 
acid in which two atoms of hydrogen have been substituted by two atoms of 
iodine (C 6 H 9 I 2 HOS0 2 OH). Iodine compounds of phenol-phthalein are known 
by the trade names of nosophen, antinosine and eudoxine. Triiodocresol is 
known as losophan, while europhen is a more complex combination of cresol 
and iodine ; loretin and vioform are derivatives of quinoline containing 
iodine. (See also under Bismuth and Alum.) These later " substitutes " for 
iodoform differ entirely from it and from iodol in the fact that iodine is not 
liberated by the tissues ; that they pass through the body unchanged, as far 
as the iodine is concerned, and that they are said to be entirely devoid of 
poisonous effects, and in fact of any action, save as local antiseptics. Their 
value as antiseptics can only be determined by further trial. They are 
almost all phenol derivatives, and any virtues they possess may prove to be 
due to this fact mainly, and not to their containing iodine. 



524 INORGANIC SALTS, ACIDS AND BASES. 

Preparations. 

Iodoformum (U. S. P., B. P.), iodoform (CHI 8 ), forms small, lemon-colored 
crystals, possessing a very penetrating, persistent and disagreeable odor and 
taste, practically insoluble in water, soluble in alcohol, ether, fixed oils, 
glycerin, etc. 0.03-0.2 G. Q-3 grs.), in pills or capsules. 

Suppositoria Iodoformi (B. P.), each containing 3 grs. of iodoform. 

Ungtjentum Iodoformi (U. S. P., B. P.), contains 10 per cent, iodoform. 

Iodol (non-pharmacopceial), a yellow crystalline powder, tasteless, odorless, 
insoluble in water. 

Aristol, a yellowish-brown powder resembling iodol in its properties. 

The Sozoiodolate of potassium is slightly soluble in water, the sodium and 
zinc salts more soluble. Mercury forms an insoluble salt which may be dis- 
solved by the addition of sodium chloride. 

Therapeutic Uses. — Iodoform has been used to a very limited extent 
internally in the treatment of syphilis, and as an intestinal disinfectant. 
It is chiefly employed in surgical treatment as an application to wounds, 
skin diseases and burns. In granulating surfaces with a profuse secre- 
tion, and in slowly healing abscess cavities, it seems to be especially 
valuable. It may be applied as a dusting powder, as an ointment, or 
in gauze or bandages saturated with it. It has been shown that it 
has very weak antiseptic properties, and many surgeons take the 
precaution of disinfecting the powder before applying it, and use it 
for its effect on the tissues of the wound and not for its effects on the 
germs. Applied in ordinary quantity to small, surfaces it seems to 
be a perfectly safe remedy, cases of poisoning occurring only when 
large cavities are plugged with it, or when it is applied to very large 
absorbent surfaces. Many attempts have been made to disguise its 
disagreeable odor, but have been attended with only moderate success. 
Among the best of the many perfumes suggested for this purpose is 
cumarin, which is contained in large quantity in the Tonka bean. 

Iodoform has been credited with some specific action in tubercular 
disease, but has proved almost inert towards the bacillus. The favor- 
able results in the local treatment of tubercular abscesses, laryngeal 
ulcers and similar conditions may with greater probability be attributed 
to its action on the granulation tissue. In syphilitic ulcers and chan- 
cres, iodoform has been used very largely and with good effects. 

Iodol may be used as a substitute for iodoform, and is applied in 
the same way. The sozoiodolates are used as powders or ointments, 
or in the case of the sodium, zinc, and mercury salts, in solution. The 
last is poisonous, and is comparable to corrosive sublimate in its effects. 

Bibliography. 

Rummo. Arch, de Phys., norm, et path., 1883, ii., p. 145. 

Binz. Arch. f. exp. Path. u. Pharm., viii., p. 309 ; xiii., p. 113. Virchow's 
Arch., lxxxix., p. 389. 

Behring. Deutsch. med. Woch., 1882, p. 278. 

Hogyes. Arch. f. exp. Path. u. Pharm., x., p. 228. 

Zeiler. Arch. f. klin. Chirurg., xxviii., p. 590. Zts. f. physiol. Chemie, viii., p. 70. 

Harnack. Berl. klin. Woch., 1883, p. 723, and 1885, p. 98. 

Falkson. Arch. f. klin. Chirurg., xxviii., p. 112. 

Neisser. Virchow's Arch., ex., p. 381. 

Freyer. Therap. Monats., 1888, pp. 287 and 334. 



FL UORIDES. 525 

Baumgarten. Berl. klin. Woch., 1887, p. 354. 

Marcus. Berl. klin. Woch., 1886, p. 342. (lodol.) 

Sattler. Fortschr. d. Med., 1887, p. 362. (lodol.) 

L&mry. Arch. f. klin. Chirurg., liii., p. 787. 

Meyer. Ibid., lv., p. 676. - 

Schmidt. Arch, internat. de Pharmacodyn. , viii., pp. Ill, 187 ; ix., p. 107. 

AUeriburg. Ibid., viii., p. 125. 

VIII. FLUORIDES. 

The fluorides present many points of difference from the other halogen 
gaits in their chemical reactions and also in their effects in the organism. 

The fluoride of sodium, which alone has been examined, possesses a power- 
fully local irritant action, which is seen most clearly when it is applied to 
the mucous membranes of the eye or of the alimentary tract. In the for- 
mer it causes congestion and inflammation of the conjunctiva and opacity 
of the cornea, when it is applied in a two per cent, solution for some time. 
Small quantities induce irritation of the stomach, nausea and vomiting, and 
the prolonged administrate u leads to irritation of the intestines and diar- 
rhoea ; solutions of the fluorides are absorbed with great difficulty by the in- 
testinal epithelium. When injected subcutaneously fluorides often induce 
inflammation and suppuration with necrosis. 

In frogs small doses induce prolonged fibrillary contractions of the mus- 
cles throughout the body, which are due to a stimulation of the terminations 
of the motor nerves. Larger doses paralyze the central nervous system and 
eventually the motor terminations, and even the nerve fibres. The muscles 
lose their irritability and pass into very marked rigor, and the heart muscle 
is also paralyzed by large quantities. 

In mammals the first symptoms are increased secretion of saliva and 
tears, acceleration and deepening of the respiration, followed by a condition 
of weakness and somnolence. Strong fibrillary tremor of the muscles then 
sets in with occasional stronger twitches, which eventually pass into attacks 
of general convulsions. In the intervals between the convulsions the animal 
lies in a state of profound coma. The respiration is finally arrested during 
an attack of convulsions, the heart continuing to beat for some time longer. 

Tappeiner found a very marked fall of blood-pressure produced by sodium 
fluoride, and attributed it to depression of the vaso-motor centre. It may 
in part account for the stupor, but this indirect action is in all probability 
strengthened by a direct depression of the higher nervous centres. The 
convulsions are central in origin, while the cause of the fibrillary contrac- 
tions in mammals is unknown. The respiratory centre seems to be first 
stimulated and then paralyzed. Muscles, nerves and other excised tissues 
die much sooner in solutions of sodium fluoride than in corresponding ones 
of the chloride, iodide or bromide, so that the fluoride ion must be assigned 
a position quite distinct from the other halogen ions in the scale of toxicity. 

The fluorides absorbed from the alimentary canal are excreted by the 
urine, but this takes place very slowly, and much of the fluoride is stored up 
in the body, some in the liver and skin, but most in the bones in the form 
of calcium fluoride. Crystals of this very insoluble salt are found in masses 
in the Haversian canals, and increase the hardness and brittleness of the 
bones. 

The prolonged administration of fluorides to animals has been found to 
cause weakness, loss of flesh, and irritation and ulceration of the gums. 

The fluoride of sodium has considerable antiseptic power, putrefaction be- 
ing delayed by the addition of one part to 500 of fluid, and one in 200 ar- 
resting completely the growth of bacteria. It has been used to a very limited 
extent as a surgical antiseptic. 

Hydrofluoric acid is an exceedingly powerful caustic, destroying the 
mucous membranes wherever it comes in contact with them. It has been 



526 INORGANIC SALTS, ACIDS AND BASKS. 

observed that workers in certain departments of* glass factories, in which the 
atmosphere contains a small amount of this acid, are very seldom attacked 
by tuberculosis, and an attempt has been made to treat pulmonary phthisis 
by the inhalation of very dilute vapors. The results have not been success- 
ful, although there is no question that hydrofluoric acid is a powerful ger- 
micide. 

Sodium fluorosilicate (SiFlNa 2 ) has also been used as an antiseptic in so- 
lution. It has been found to cause nausea, eructation and slowness of the 
pulse when swallowed. 

Bibliography. 

Tappeiner. Arch. f. exp. Path, u. Pharm., xxv., p. 203; xxvii., p. 108. 

Schulz. Ibid., xxv., p. 326. 

Hewelke. Deutsch. med. Woch., 1890, p. 477. 

Langgaard. Therap. Monatsh., 1888, p. 178. 

Gottbrecht. Ibid., 1889, p. 411. 

Brandl u. Tappeiner. Ztschr. f. Biologic, x., p. 518. 

Bokenham. Brit. Med. Journ., 1890, p. 355. 

Mulkr. Inaug. Diss., Greifswald, 1889. 

Siegfried. Arch, internat. de Pharmacodyn. , ix., p. 225. 

IX. CHLORATES. 

The chlorate of potassium, introduced into therapeutics on the erro- 
neous theory that it would supply oxygen to the tissues, has been used 
very extensively for its effects in certain diseases of the mouth. It 
was supposed to be entirely devoid of poisonous properties, but has 
given rise in a considerable number of instances to very grave, and 
even fatal symptoms. In such cases the symptoms are due partly to 
the salt-action, but chiefly to the specific effects of the chlorate ion. 
The chlorate of sodium induces these chlorate symptoms, and the 
chlorate of ammonium is said to be the most poisonous of the three. 
It would seem that the conditions which determine their appearance 
are not universally present, for very often large quantities have been 
taken with impunity, while in other individuals much smaller quanti- 
ties have induced grave poisoning. 

Symptoms. — The chlorates have a cool, saline taste, which persists 
for a long time owing to their being excreted in part in the saliva. 
Concentrated solutions may cause nausea and vomiting from their local 
salt-action in the stomach, and their absorption is often followed by 
considerable diuresis from a similar action in the kidney. In the 
great majority of cases no further effects are observed. 

In some individuals, however, symptoms arise from the chlorate 
action quite apart from those mentioned above, which may be induced 
by chloride of sodium or, in fact, by any other diffusible salt. (See 
Salt-action, page 485.) These chlorate symptoms may be divided into 
those of acute and of subacute poisoning, the first arising generally from 
the administration of a single large dose, the second from smaller 
quantities taken repeatedly. In Acute Chlorate Poisoning the first 
symptom is often prolonged and violent vomiting, with pain in the 
stomach region ; diarrhoea and a dark cyanotic color of the skin and 
mucous membranes follow, the respiration is at first dyspnoeic and then 
weak, the pulse quick and feeble, sometimes irregular. The patient 



CHLORATES. 527 

complains of headache, giddiness and muscular weakness, is restless, and 
eventually becomes comatose before death. 

In Subacute Poisoning, vomiting and diarrhoea are also observed, 
and the vomited matter often contains large quantities of bile, less 
often blood. There may be complete anuria for some time, or the 
urine is scanty and at first dark colored, then deep reddish-brown ; 
it contains haemoglobin, methaemoglobin, and haematin in solution. 
On standing, it deposits casts of brown amorphous particles, which arise 
from the destruction of the red cells of the blood, and chlorates are 
contained in it in considerable quantity. The methaemoglobin may 
disappear from the urine after one or two days, but the casts re- 
main longer. The skin is often icteric in color, and in some cases 
erythematous eruptions have been observed. Headache, muscular weak- 
ness and abdominal pain are complained of, and uraemic symptoms may 
arise — delirium and convulsions, or confusion and coma. Death has 
followed from these last as late as a week after the first symptoms of 
poisoning were observed, but in several cases complete recovery has 
followed even the gravest symptoms. 

Action. — The cause of the symptoms in acute and subacute chlorate 
poisoning is, apart from the salt-action, a specific effect which the 
chlorates have on the Red Blood Cells and particularly on the Haemoglo- 
bin. This is seen especially well when blood is added to a chlorate 
solution outside the body, for in the course of a short time the blood 
assumes a dark chocolate brown color, and spectroscopic examination 
reveals the absorption bands of methaemoglobin and often of haematin. 
After a time the red blood cells tend to break up, and the methsemoglo- 
bin is freed in the serum. If large quantities of chlorate be added, 
the blood becomes quite black in color, and assumes a gelatinous con- 
sistency. This action of chlorates on the blood was formerly supposed 
to be due to their oxidizing the haemoglobin and being themselves re- 
duced to chlorides, but this has been shown to be erroneous, for the 
chlorates remain unchanged and methaemoglobin is not a simple oxida- 
tion product of haemoglobin. 

When this transformation of the haemoglobin takes place in ves- 
sels, the blood is unable to supply the tissues with oxygen, because in 
methaemoglobin the oxygen is attached much more firmly than in oxy- 
hemoglobin, and the tissues are incapable of availing themselves of it. 
If much of the haemoglobin is thus rendered useless, asphyxia results, 
and this is unquestionably the chief cause of the symptoms and of the 
fatal issue in the most acute form of intoxication. If a smaller amount 
of methaemoglobin is formed, it disappears gradually, either by being 
slowly reformed to haemoglobin, or by the corpuscles containing it 
being withdrawn from the circulation and broken up. When a con- 
siderable amount of haemoglobin is transformed, but sufficient remains 
to continue the respiration of the tissues, the subacute form of poison- 
ing results. The blood cells break up and the haemoglobin, methaemo- 
globin and the debris of the corpuscles thus freed in the plasma are 
in part excreted by the urine, in part deposited in the spleen, liver, 



528 INORGANIC SALTS, ACIDS AND BASES. 

and bone marrow. As in other conditions of excessive destruction of 
the red blood cells, the bile pigment is increased in amount, and its 
absorption from the bile capillaries induces jaundice. The excretion 
of the products of the destruction of the red blood corpuscles in the 
urine leads to the renal tubules becoming stopped up with brown 
granular masses, which are in part forced downwards and appear in 
the urine as casts, but which may lead to an almost complete suppres- 
sion of urine and to symptoms of ursemic poisoning. In those cases in 
which death follows several days after the first symptoms, it seems due 
not to the direct action of the poison, but to the renal changes. Often 
no actual nephritis is present, but in some cases the epithelial cells 
seem to be inflamed, probably as a secondary result of the plugging 
of the tubules. The deposition of the debris in the liver and spleen 
often causes enlargement of these organs. In these subacute cases of 
poisoning, then, death is not due directly to the methsemoglobin for- 
mation, but to the breaking down of the red cells. The connection 
between these two processes has not been explained as yet, but there 
seems every reason to believe that one exists. In the case of the 
chlorates the haemoglobin transformation apparently precedes the de- 
struction of the corpuscles. 

The post-mortem appearances in chlorate poisoning vary with the 
form. In acute poisoning the characteristic color of the blood, and 
the methsemoglobin absorption band in the spectrum are often the only 
distinct appearances. In less acute cases, the debris of the red cor- 
puscles is found in the liver, spleen, bone-marrow and renal tubules, 
while no methsemoglobin may be detected. Some of the red blood 
corpuscles are found misshapen, however, others are colorless (shadows), 
and in some the pigment is formed in masses, instead of being gener- 
ally diffused. Some swelling and ecchymoses of the gastric and in- 
testinal mucous membrane have been observed. 

It has been recently stated that some of the symptoms of chlorate 
poisoning are due to infarcts formed in the smaller vessels from the 
agglutination of the remains of the red-blood cells, and Silbermann 
has even failed to inject some parts of the body owing to this plugging 
of the arteries. This statement has been denied, however, by Mar- 
chand and Falkenberg, who could find no evidence of such infarction. 

The haemoglobin of most animals seems equally easily transformed 
to methaemoglobm by chlorates when it is dissolved in water, but the 
blood corpuscles of the rabbit and guinea-pig resist their action much 
more than do those of the dog and of man. Rabbits therefore very 
rarely show any symptoms of true chlorate action, and die of the 
potassium or of the salt-action, while dogs and cats exhibit symptoms 
very like those seen in man. The cause of this immunity of the 
rabbit's corpuscles is unknown, but may perhaps be explained by their 
being impermeable by the chlorate salts. It has been found that when 
the rabbit's blood is concentrated, or when bile is present in quantity 
in it, the chlorate action may be elicited much more readily than in 
normal animals. 



CHLORATES. 529 

The nervous symptoms in chlorate poisoning are manifestly due to 
the blood changes and the uraemia for the most part, though there is 
reason to believe that under some conditions the brain is also directly 
affected. The heart is said to be first slowed and then accelerated by 
the intravenous injection of sodium chlorate. The vomiting does not 
seem to be due to local action only, for it is seen in animals in which 
the salt is injected subcutaneously. 

The chlorates are not reduced in the blood and tissues as was for- 
merly supposed, for 90-96 per cent, of the amount administered has 
been recovered from the urine. Small quantities appear also in the 
saliva and in other secretions such as the perspiration, milk, tears, 
and nasal mucus, and some has been found to pass from the mother to 
the foetus in utero. 

The chlorates are hardly more antiseptic than other indifferent 
salts. 

The Bromates and Iodates have been much more seldom the subject of in- 
vestigation than the chlorates, and are not used in therapeutics. The iodates 
are more poisonous than the bromates and these again than the chlorates, 
though the chlorates are much more powerful blood poisons than the others. 
Iodates induce fatty degeneration of the liver, and congestion and extra- 
vasation in the alimentary tract. It is not unlikely that some iodide is 
formed from them in the body. 

The action of the Perchlorates has been examined by Kerry and Rost. 
In the frog the perchlorate of sodium (NaClOJ induces fibrillary twitching 
and clonic contractions of the muscles ; the contraction of the muscle is pro- 
longed in the same way as by veratrine, and rigor eventually follows as in 
caffeine poisoning. The reflex excitability is increased, and the heart is slow 
and irregular. The effects of the perchlorate on mammals differ consider- 
ably in different species ; in the rat, mouse and guinea-pig the reflex excita- 
bility is enormously increased and tetanic convulsions may arise from this 
action ; in the cat a certain stiffness, muscular paresis and tremor can be 
made out after the injection of large quantities of perchlorate, but these 
animals as well as the rabbit and dog are not killed by even very large 
quantities. 

Preparations. 

Potassii Chloras (U. S. P., B. P.) (KClOg), 0.3-1 G. (5-15 grs.). 

Trochisci Potassii Chloratis (U. S. P.) contain 0.3 G. (5 grs.) chlorate 
of potassium in each lozenge. 

Trochiscus Potassii Chloratis (B. P.) contains 3 grs. in each. 

Sodii Chloras (U. S. P.) (NaC10 3 ), 0.5-2 G. (10-30 grs.). 

The chlorates are colorless prismatic crystals with a saline taste, and are 
given in solution or in lozenges when used internally. The dry salts form 
explosive mixtures with organic or other reducing substances, and such 
mixtures are therefore to be kept cool, and ought not to be ground together, 
as heat and pressure are liable to cause explosions. 

Therapeutic Uses. — The chlorate of potassium is used chiefly as a 
mouth wash and gargle in irritable conditions of the mouth and throat, 
such as aphthe, and in the tenderness and ulceration of the gums and 
mouth induced by the prolonged use of mercury. It may also be 
given as a prophylactic to prevent stomatitis when mercury is being 
prescribed, but it does not prevent the salivation. In catarrh of the 
throat the chlorate of potassium is often used with apparently good 
34 



530 INORGANIC SALTS, ACIDS AND BASES. 

effects. It has been strongly advised in diphtheria, but is of only 
questionable value here. 

The chlorate of potassium is more frequently prescribed than the 
sodium salt, but the latter seems equally efficient. The chlorates are 
used in 2-4 per cent, solution, or the official lozenge may be prescribed. 
In children a somewhat stronger solution with syrup or honey may be 
used to brush out the mouth, but care should be taken that none is 
swallowed. The local action of the chlorates has not been explained, 
and it may be due to the salt-action in part, though not wholly. It has 
been suggested that they are oxidizing disinfectants, but there is no 
reason to suppose that they are changed here any more than in the tis- 
sues in general. It is not impossible that equally satisfactory results 
might be obtained by the use of the chlorides or nitrates. Chlorate of 
potassium has been given internally in cases of diphtheria and in some 
diseases of the mouth, but it does not seem to have any therapeutic 
value unless when applied locally. Some benefit may arise from its 
contact with the mouth and throat in the process of swallowing and 
from its excretion in the saliva. In addition the internal administra- 
tion of the chlorate is liable to induce dangerous poisoning. It is un- 
necessary to discuss the earlier uses of the chlorate, which were based 
on the theory that it gave up its oxygen to the blood, for both theory 
and practice have been shown to be erroneous. 

Poisoning. — The fatal dose of chlorate varies extremely, as little as 
4 G. (60 grs.) having proved fatal in a child, while 40-50 G. (10-12 
drs.) have been swallowed by adults without marked symptoms. There 
is no question that the red blood cells are often peculiarly susceptible 
to the action of the chlorates. In cases of poisoning the stomach should 
be evacuated, if any of the salt is believed to remain in it, but the symp- 
toms often appear only 2—3 hours or longer after the drug has been 
taken. General treatment with central nervous stimulants, ice for the 
vomiting, etc., may be carried out. The destruction of the blood cells 
is believed to be less liable to occur when the blood is more alkaline 
than usual, and this has led to the administration of the alkaline car- 
bonates in these cases. After the acute symptoms pass off, diuretics 
are often advised, and large quantities of fluid are given, in order to 
flush out the kidneys, and prevent as far as possible the tubules from 
being stopped up by detritus. 

Bibliography. 

Marchand. Virchow's Arch., lxxvii., p. 455. Arch. f. exp. Pathi u. Pharm., 
xxii., p. 201 ; xxiii., pp. 273 and 347. 

Mering. Das chlorsaure Kali, 1885, Berlin. 

Stokvis. Arch. f. exp. Path. u. Pharm., xxi., p. 169. 

Cahn. Ibid., xxiv., p. 180. 

Limbeck. Ibid., xxvi., p. 39. 

Lewin u. Posner. Centralbl. f. d. med. Wissensch., 1887, p. 354. 

Dittrich. Arch. f. exp. Path. u. Pharm., xxix., p. 247. 

SUbermann. Virchow's Arch., cxvii., p. 288. 

Falkenberg. Ibid., cxxiii., p. 577. 

Binz. Arch. f. exp. Path. u. Pharm., x., p. 153; xxxiv., p. 185. 

Jawein. Virchow's Arch., clxi., p. 461. 



NITRATES. 531 

Falck. Pfluger's Arch., xlv , p. 304. 

Dreser. Arch. f. exp. Path. u. Pharm., xxxiv., p. 204. (Iodates, Bromates.) 

Kerry u. Host. Ibid., xxxix., p. 144. (Perchlorates. ) 

X. NITRATES. 

The nitrates are generally supposed to have little action except that 
of salts in general, and have been comparatively seldom the subject of 
pharmacological examination. In small doses they induce changes 
very similar to those seen after the chlorides, but there is little doubt 
that in addition to the salt-action, a distinct nitrate-ion effect exists, 
and is manifested chiefly in irritation of the mucous membranes which 
are exposed to it. 

Symptoms. — The nitrates have a cool, saline taste, and in small 
doses induce no symptoms save an augmented flow of urine. Large 
quantities, however, cause gastro-intestinal irritation, giving rise to 
pain in the stomach region, nausea, vomiting and sometimes diarrhoea, 
and blood may be present in the vomited matter and in the stools. 
The urine is often abundant, but may be scanty or entirely suppressed. 
These symptoms may be followed by great muscular weakness, apathy, 
collapse and eventually coma and death. When potassium nitrate is 
the drug taken, the symptoms of heart weakness are especially 
marked. 

At the autopsy the stomach and intestines are found red and con- 
gested, and very often contain blood extravasations. The kidney is 
said to have presented the symptoms of acute nephritis and haemor- 
rhages in some cases of poisoning. 

When dilute solutions of the nitrates are used, much less irritation 
is induced, and in fact large quantities may be taken thus without 
causing any symptoms whatever except diuresis. 

Action. — Very similar effects may be induced by large quantities of 
common salt, or of potassium chloride, and it is therefore often stated 
th.it the nitrates act in the same way as the chlorides. But this is not 
entirely correct, for while there is no question that the salt-action ex- 
plains much of the effect of the nitrates, these salts have a specific 
irritant action. Thus very much smaller quantities of the nitrates 
than of the chlorides are sufficient to induce serious irritation, and 
solutions of the nitrates isotonic with the blood induce irritation and 
congestion in the intestine and are slowly absorbed. This irritant 
effect of the nitrates has been explained by Binz and Barth as the 
result of the reduction of the nitrates to nitrites in the alimen- 
tary canal and tissues, but no symptoms of nitrite action seem 
to have been observed in cases of poisoning with nitrates. Haldane 
has recently shown that nitrite is formed from the nitrate used in 
the preservation of meat by salting, and that some nitrous-oxide 
haemoglobin is formed and gives a bright red color to the meat. 
The presence of this pigment may perhaps explain the red color of 
the intestine in some cases of poisoning in which extravasations of 
blood are not marked. 



532 INORGANIC SALTS, ACIDS AND BASES. 

The nitrates have long been used as diuretics, more especially the 
nitrate of potassium. The diuresis is generally attributed to the salt- 
action, but there may be in addition a true stimulation of the kidney 
similar to that observed under the action of many other drugs which 
are irritant to the bowel. If WeyPs statement be correct that the 
nitrates of the urine are not increased by the administration of nitrates 
by the mouth, the diuresis must be due to some stimulant action only. 
The nitrate of potassium is generally considered a better diuretic than 
the sodium salt. 

The Fate of the Nitrates in the Body is still unknown, and in fact 
seems to vary in different animals and under different conditions. In 
man and in most animals, some nitrate is present in the urine normally, 
apparently derived from vegetable food, although it may in some cases 
be one of the final products of the proteid metabolism. When nitrates 
are given by the mouth, however, no corresponding increase in the 
amount excreted in the urine occurs. Some of that given generally 
appears in the urine, but more than half of it disappears entirely in 
the tissues. According to Weyl 1-3 G. of nitrate of potassium admin- 
istered to patients causes no increase whatever in the nitrate excreted 
in the urine, the whole of it being changed into some other form in 
the organs. It is surmised that the nitrate is reduced first to the 
nitrite, and then to ammonia, or that it is eventually excreted by the 
lungs as free nitrogen. Some of the nitrate seems to be excreted in 
the saliva and perspiration, possibly unchanged, although it is rapidly 
reduced to nitrite in these secretions, and may in fact be changed to 
this form in the secretory cells. In the dog a considerable proportion 
of the nitrates ingested appears again in the urine, and it is to be noted 
that earlier investigators did not find the nitrates disappear entirely in 
man as Weyl did. 

The action of the nitrates on the individual organs is practically 
entirely unknown. They are said to have some effect on the red blood 
cells, which became crenated, but this is probably merely the salt- 
action and not any specific nitrate effect. 

Richet has found solutions of the nitrate of sodium less harmful to 
fish living in it than those of any other salt except the chloride. 

Preparations. 

Potassii Nilras (U. S. P., B. P.), Nitre, Saltpetre (KN0 8 ), 0.3-2 G. (5-30 
grs.). 

Sodii Nitras (U. S. P.), Chili saltpetre (NaN0 3 ), 0.3-2 G. (5-30 grs.). 

Charta Potassii Nitratis (U. S. P.), paper impregnated with saltpetre. 
When burned it gives off a dense smoke containing pyridine and other 
similar bodies and perhaps some nitrite combinations. 

The nitrates form colorless crystals with a cool, saline taste. They are 
very soluble in water and are prescribed in dilute solution. 

Therapeutic Uses. — The nitrates are seldom used now except as in- 
gredients of diuretic mixtures ; e. g., along with digitalis. The nitrate 
of potassium was formerly employed largely in fevers and in various 
disorders of the metabolism, such as rheumatism or gout, but in none of 



SULPHITES. 533 

these has it been found useful. The nitrates are to be given with care 
when there is any irritation of the stomach and intestine. Authorities 
differ as to whether they may be prescribed in irritation of the kidney, 
but in every case they ought to be well diluted. 

The saltpetre paper is used in asthma by burning it in the sick 
room, when the pyridine and other bodies relieve the spasms. Salt- 
petre may be used in cigars or cigarettes for the same purpose, and 
the tobacco may contain also the leaves of belladonna or some of its 
allies, as these have a special action on the bronchial muscles. 

Bibliography. 

Earth. Schmidt's Jahrb., clxxxii., p. 286. 

Littlejohn. Edinburgh Med. Journ., 1885, p. 97. 

Eoehmann. Zts. f. physiol. Chem., v., p. 233. 

Weyl. Virchow's Arch., xcvi., p. 462 ; ci., p. 175; cv., p. 187. 

Eichet. Comptes rend. d. 1. Soc. de Biol., 1886, xxxviii., p. 486. 

Mairet et Combemale. Ibid., 1887, xxxix., pp. 57 and 63. 

Haldane. Journ. of Hygiene, i., p. 115. 

Eost. Arch. f. [Anat.u.] Physiol., 1901, p. 534. 

XI. SULPHITES. 

The sulphites, an unimportant group of bodies from a therapeutic point 
of view, have been shown to have a more poisonous action than many better 
known salts. They possess fairly strong antiseptic properties, because they 
withdraw oxygen from organic matter in order to oxidize themselves to sul- 
phates. Injected into frogs, sulphite of soda causes great muscular weak- 
ness and depression, and eventually paralysis of the central nervous system, 
beginning in the brain and descending to the spinal cord. Later, the heart 
becomes weak and ceases in diastole, and the peripheral nerve terminations 
and the muscles are paralyzed. In mammals the action is exerted chiefly 
on the medulla oblongata and the heart. In the dog and cat subcutaneous 
injection causes nausea, vomiting, restlessnesss and dyspnoea and great 
muscular weakness, ending in arrest of the respiration, and a little later of 
the heart. In the rabbit the symptoms consist of dyspnoea, muscular weak- 
ness without loss of spontaneous movements, and finally death from failure 
of the respiration and the heart. 

Much larger quantities are required to poison animals when given by the 
mouth than when injected subcutaneously, probably because the salt is 
slowly absorbed from the alimentary tract, and also because some of it is 
changed to the harmless sulphate before it reaches the blood. Some irri- 
tation of the stomach is caused from the sulphurous acid being freed by the 
gastric juice, and this induces vomiting in the dog. 

Intravenous injection shows that the chief seat of action of the sulphites is 
the medulla oblongata, in which they depress the respiratory and vasomotor 
centres. The heart is acted on directly apparently, for the pulse is slow, 
and the muscular walls of the vessels are also weakened. Kionka states 
that sulphites destroy the red cells of the blood, and that infarcts are formed 
from their remains in the vessels and lead to haemorrhages in many organs. 

If large quantities be absorbed rapidly, they prove immediately fatal, but 
if the respiration be kept up for a short time, recovery may follow, because 
the poisonous sulphite is changed to the harmless sulphate and excreted. 
About 96 per cent, of the sulphite absorbed into the blood is oxidized to the 
sulphate, while some 3 per cent, is excreted in the urine unchanged. The 
thiosulphate is apparently oxidized with greater difficulty, for Walko found 
30-50 per cent, eliminated by the kidneys unaltered. 



534 INORGANIC SALTS, ACIDS AND BASKS. 

Large doses of sulphites have been taken by man without symptoms of 
poisoning being induced. Even 30-40 gms. are said to have been swallowed 
but in most preparations of sulphite a large proportion of sulphate is pres- 
ent, and it is impossible to state how much sulphite was really contained in 
these doses. Symptoms of gastric and intestinal irritation have been in- 
duced by comparatively small quantities, and Kionka found that even smaller 
doses of sulphite administered daily to animals caused haemorrhages in dif- 
ferent organs, and accordingly condemns the use of sulphites to preserve 
meat, wines and vegetables ; in addition they seem to have little effect in 
preserving meat from putrefaction. 

Sodii Sulphis (IT S. P., B. P.) (Na 2 S0 3 -f- 7H 2 0), a soluble salt which oxi- 
dizes to the sulphate in the air, is feebly alkaline and has a cool, saline 
taste. 0.3-2 G. (5-30 grs.). 

Sodii Bisulphis (U. S. P.) (NaHS0 3 ) has a disagreeable odor of sulphurous 
acid, an unpleasant taste and an acid reaction. -1-2 G. (15-30 grs.). 

Sodii Hyposulphis (U. S. P.) (Na 2 S 2 3 + 5H 2 0) is not the true hyposul- 
phite, but the thiosulphate of sodium. It is very soluble, has a cool, saline 
taste and is neutral in reaction. 1-2 G. (15-30 grs.). 

Solutions of these salts have been used to a limited extent as antiseptic 
mouth-washes in aphthe, and have been prescribed in some forms of fermen- 
tation in the stomach. They were formerly reputed to be of benefit in cases 
of pyaemia from their supposed action as antiseptics in the blood, but have 
never been shown to be of any real value. 

Bibliography. 

Pfeiffer. Arch. f. exp. Path. u. Pharm., xxvii., p. 261. 
Kionka. Ztschr. f. Hygiene, xxii., p. 351. 
Walko. Arch, de Pharmakodynam,, iv., p. 311. 
Lange. Arch. f. Hygiene, xl., p. 143. 

XII. HYPOPHOSPHITES. 

The hypophosphites have been used in therapeutics in the belief that they 
had some special influence on nutrition. They were formerly supposed to 
be oxidized in the tissues to the phosphates, but this has been shown to be 
incorrect, as practically the whole of the hypophosphite administered can 
be recovered unchanged from the urine. No entirely satisfactory work on 
the effects of these salts on the nutrition has been done, but there is no 
ground to suppose that they have any further action than the other indif- 
ferent salts, such as the chlorides. The chief effect of the hypophosphite of 
iron is undoubtedly due to the metallic ion. 

Preparations. 

Sodii Hypophosphis (NaOPH 2 0) (IT. S. P., B. P.), 0.2-0.6 G. (3-10 grs.). 

Potassii Hypophosphis (KOPH 2 0) (U. S. P.), 0.2-0.6 G. (3-10 grs.). 

Calcii Hypophosphis (Ca(OPH 2 0) 2 ) (U. S. P., B. P.), 0.2-0.6 G. (3-10 grs.). 

Ferri Hypophosphis (Fe 2 (OPH 2 0) 6 ) (TJ. S. P.), 0.2-0.6 G. (3-10 grs.). 

Syrupus Hypophosphitum (U. S. P.) contains the hyphophosphites of cal- 
cium, potassium, sodium, free hypophosphorous acid, spirit of lemon and 
sugar, 4-8 c.c. (1-2 fl. drs.). 

Syrupus Hypophosphitum cum Ferro (U.S. P.) contains the syrup of hypophos- 
phites along with lactate of iron and citrate of potash, 4-8 c.c. (1-2 fl. drs.). 

Therapeutic Uses. — The hypophosphites are used in weakness and ca- 
chexia, and especially in commencing phthisis and anaemia. The syrup with 
or without iron is the form in which they are invariably prescribed. There 
is a popular belief that they improve digestion and nutrition, but most re- 
liable investigators deny that they have any other influence than the better 
known and cheaper salts of iron, calcium, etc. 



SALINE CATHARTICS. 535 

Bibliography. 

Paquelin et Joly. Comptes rendus de l'Acad. d. Science, lxxxvi., p. 1505. 

Taylor. Lancet, 1861, ii., p. 517. 

Boddaert. Arch. d. Pharmacodynam., ii., p. 195. 

Gamier. Kev. Med. de Test, 1896, p. 257. 

XIII. SALINE CATHARTICS. 

Dilute solutions of such salts as the chlorides, iodides and bromides 
of the alkalies are absorbed rapidly from the alimentary canal, but 
some of the other salts of these metals apparently permeate the epi- 
thelium with greater difficulty, and their solutions therefore remain 
unabsorbed for a longer time in the intestine. Little is known of the 
effects of these salts in the tissues, but their action in the intestine 
has led to their therapeutic use, and they may therefore be classed to- 
gether as the saline cathartics, in order to distinguish them from the 
rapidly absorbed salts, such as the chlorides, or bromides. The chief 
salts of sodium and potassium which have this intestinal action are the 
sulphates, phosphates, tartrates and citrates ; less known ones are the 
malates and ferrocyanides. 

It is manifest that the peculiar effect of these salts is due to the 
acid constituent, or anion, and not to the base or kation, for the latter 
may be present in readily absorbable salts, such as chlorides. All 
combinations in which the sulphate, phosphate, etc., ion is found, 
therefore, are less easily absorbed than the corresponding ones with 
bromide or chloride ions. But these cathartic anions are only weakly 
active, and no pronounced difference can be observed in the action of 
chlorides and sulphates, unless the salt can be given in large quanti- 
ties, as is possible in the case of the salts of the alkalies. The effects 
of the sulphate and hydrochlorate of morphine, for example, may be 
taken as identical, because the anion is present in so small amount as 
to be practically inert. 

The chloride ion is rapidly absorbed, as is seen in the case of sodium 
chloride. Yet when the chloride of magnesium is administered, it 
disappears only very slowly from the bowel. It would seem, there- 
fore, that the magnesium is also more slowly absorbed than the sodium 
and potassium ions, and that cathartic action can be' obtained from 
either basic ions (kations) or from acid ions (anions). When both 
ions of a salt are slowly absorbed, the cathartic is, of course, more power- 
ful than when one is rapidly absorbed. Thus, magnesium sulphate is 
a more powerful purgative than either magnesium chloride or sodium 
sulphate, because in the first both ions are difficult of absorption, while 
in the others only one is cathartic. It seems probable that all the 
alkaline earth ions resemble magnesium in permeating the epithelium 
with difficulty. 

The chief saline cathartics used in therapeutics are the sulphate of 
sodium (Glauber's salt), the sulphate of magnesium (Epsom salt), the 
double tartrate of sodium and potassium (Rochelle salt) and the ci- 
trates of potassium and magnesium. In addition the oxide and car- 



530 INORGANIC SALTS, ACIDS AND BASES. 



bonate of magnesium have some purgative action from being formed 
into soluble salts in the stomach and intestine. But besides these 
many other salts are slowly absorbed and might therefore be used for 
this purpose. Thus the sulphates, citrates, or tartrates, of any of the 
alkalies or of the non-poisonous alkaloids might be used for this purpose, 
provided they are soluble, and any of the magnesium salts might be 
used in the same way. 

Symptoms. — The external application of solutions of the saline 
cathartics has the same effect as that of any other indifferent salt, such 
as sodium chloride (see page 491). 

Most of the cathartics have a harsh, bitter, unpleasant taste, and 
when taken in concentrated solution, may induce some nausea, partly 
from the taste, and partly from their effect on the stomach, which is 
the same as that of solutions of sodium chloride of similar concentra- 
tion. Dilute solutions, however, provoke no such symptoms, but after 
one or two hours induce a profuse watery evacuation of the bowels. 
This is sometimes preceded by some pain and griping, but these are 
not nearly so frequent or so severe as after the vegetable purgatives. 
Not infrequently the urine is increased in amount afterwards, or it may 
be found to have an unusually high percentage of salts. If a moderate 
quantity of a dilute solution be given, only one evacuation follows, but 
large doses of concentrated solutions induce repeated stools, which at 
first contain some faecal matter, but later consist mainly of bile-stained 
mucous fluid. 

Action : Intestine. — The explanation of the action of the saline 
cathartics has been much debated, and the details have not even yet 
been entirely settled. One point is, however, perfectly certain — the 
saline cathartics differ from the vegetable purgatives in not inducing 
irritation of the intestine, unless when they are given in very large 
quantities. The characteristic effect is not irritation, but retarded ab- 
sorption. If a solution of sodium chloride isotonic with the blood 
serum be administered by the mouth to a dog with a csecal fistula, 
little or none of it reaches the wound, as it is all absorbed in the 
stomach and small intestine. If, on the other hand, an equal amount 
of an isotonic solution of sodium sulphate be administered in the 
same way, the most of the solution escapes by the fistula, only some 
10—20 per cent, having been absorbed by the stomach and small in- 
testine. In a normal dog or in the human subject, a much larger 
amount of fluid therefore reaches the large intestine if sodium sulphate 
be dissolved in it than if sodium chloride be used instead. The con- 
tents of the large intestine are consequently more fluid than usual, and 
are passed down more easily towards the rectum. At the same time 
the weight and distention of the bowel induces increased peristalsis 
and the whole is evacuated. This increased peristalsis is due, how- 
ever, not to any irritant action such as has been found to be induced 
by rhubarb or croton oil, but to the large amount of fluid contents. 

If a weaker solution of sodium sulphate is administered, the only 
difference is that more of the fluid is absorbed and less reaches the 



SALINE CATHARTICS. 537 

large intestine ; but however weak the solution, more of it reaches 
the large intestine than if a correspondingly weak solution of common 
salt had been given. 

If a hyperisotonic solution be administered, the effect is somewhat 
different. The salt is still unabsorbed, but it draws fluid from the 
blood into the bowel from its having a higher osmotic pressure than 
the blood. A similar draining of the body fluids occurs when con- 
centrated solutions of common salt reach the bowel, but the cathartic 
salts are much more powerful, because they do not pass out of the bowel 
into the blood so easily. Instead of an exchange of salt and fluid 
being carried on by the blood and intestinal contents, the blood gives 
up its fluid without any sufficient compensation in salt. Eventually 
the intestinal fluid becomes isotonic, and then some absorption of both 
salt and fluid occurs ; in fact, some salt has been absorbed all along, as 
the epithelium is not absolutely impermeable to the cathartics. But 
much less of the sulphate is absorbed than of the chloride given in 
equal concentration, and as a general rule a strong solution causes 
such an accumulation of fluid that the bowel becomes distended and 
evacuates its contents. If, however, from any cause this fails to occur, 
a gradual absorption follows and the whole of the salt and fluid in the 
bowel is absorbed. These salts may fail to purge, for example, when 
the blood and tissues contain very little fluid, as in animals which have 
been deprived of water for several days previously. In this case the 
osmotic pressure in the bowel is unable to draw fluid from the concen- 
trated blood, which on the other hand has a higher attraction for the 
iluid in the bowel than usual. But where large quantities of fluid are 
present in the tissues, as in oedema and dropsy, the saline cathartics 
drain them through the blood into the bowel, and very profuse evacu- 
ation occurs, with the disappearance of the exudate. 

There is still some doubt as to why the saline cathartics are so slowly 
absorbed from the intestines. According to one school, which believes 
that in addition to the physical forces a distinct cellular activity plays 
a part in the absorption, the saline cathartics depress the living matter 
of the cell. Another theory is that the saline cathartics fail to pene- 
trate into the cell, exactly as the salts of the metals fail to penetrate 
the red blood cells, that there is a distinct affinity between the bowel 
epithelium and the chloride of sodium, but only a much weaker one 
between it and the cathartics, which therefore fail to permeate it. The 
latter view is probably the correct one, although there are still diffi- 
culties to be explained before it can be accepted as entirely satisfac- 
tory. Its acceptance does not involve the rejection of the belief that 
the cell is actively engaged in absorption, for it is difficult to explain 
how a solution after penetrating the superficial layers of the epithelium 
is passed on from them to the blood except by assuming that the cell 
exercises some propelling force, which maybe exerted only during its life. 

The further question arises, why the intestinal epithelium should be 
permeable by certain salts such as the chloride of sodium and imper- 
meable by others (sulphate of sodium). In this relation it has been 



538 INORGANIC SALTS, ACIDS AND BASES. 

found by Hofmeister that the purgative salts have a greater tendency 
to precipitate proteids and have less tendency to permeate into unor- 
ganized colloids than most of the non-purgative salts. Another curi- 
ous relation between the purgative anions is that their calcium salts 
are all very much less soluble than those of the salts which penetrate 
the epithelium, but whether this is merely a coincidence or not is un- 
certain. Most of the cathartic anions are bivalent or trivalent, but 
this is not true for all of them, for the higher members of the acetate 
series are absorbed with the greatest difficulty by the intestine. 

The saline cathartics induce certain changes in the Blood indirectly- 
through their action on the intestine. They prevent the absorption of 
the fluid of the food, or, if in sufficient concentration, actually draw 
fluid from the blood and tissues into the bowel, and under both condi- 
tions the blood becomes more concentrated than usual ; in the first 
case because it is not reinforced by the usual amount of fluid from the 
food, in the second because it actually loses fluid into the intestine. 
This concentration of the blood leads to a sensation of thirst, and to a 
lessened excretion of fluid by the kidneys and other glands. 

A certain amount of salt and of fluid is absorbed from the intestine,, 
unless purgation follows very rapidly, and this salt acts in the blood 
and tissues in the same way as the salts which do not act as cathartics. 
When very dilute solutions of these salts are given, therefore, the effect 
is similar to that of ordinary salt, except that the hydremia and the 
diuresis do not follow so soon, because the absorption is somewhat 
slower. Stronger cathartic solutions at first cause a concentration of 
the blood and lessened urine, but afterwards the excess of salt in the 
blood may cause diuresis. The greater the purgative action, the less 
the diuretic, because more fluid and more of the cathartics are thrown 
out in the stools. If no purgation follows for any reason, as when the 
blood has been concentrated by long abstinence from water, the whole 
of the salt eventually passes into the blood and is excreted by the kid- 
ney, and may cause very considerable diuresis and a still further con- 
centration of the blood. The sulphates are absorbed by the epithelium 
of the renal tubules with much greater difficulty than chloride, and 
thus offer osmotic resistance to the absorption of the fluid in the tubules ; 
sulphates absorbed into the blood therefore induce a more diffuse diuresis 
than an equal amount of chloride, but less of the former reaches the 
blood generally, so that the chlorides are better practical diuretics. 

From the above it can be at once inferred that a saline cathartic in- 
jected intravenously causes no purgation, for instead of preventing the 
passage of fluid from the bowel into the blood, it rather encourages its 
absorption by increasing the osmotic pressure of the blood. And this 
has been shown to be the case by repeated experiment. One fact which 
seems to be opposed to this explanation is that the saline cathartics 
sometimes cause purgation when injected in very small quantity into 
the subcutaneous tissues of the abdomen. But this is due not to the 
specific action of the drug, but to its causing pain and inflammation, 
and in fact acting as a counter-irritant (Hay). 






SALINE CATHARTICS. 539 

The statement is sometimes made that the saline cathartics act as 
cholagogues, i. e., increase the secretion of bile, but this has been shown 
to be erroneous by a series of careful observations. 

The Temperature is often somewhat reduced by the action of the 
saline cathartics, but seldom more than one half degree. 

The habitual use of saline cathartics is often efficient in Reducing 
the Weight in obesity, and many of the natural mineral waters have 
a considerable reputation in the treatment of such cases. The way in 
which they act is not understood, for though there is often somewhat 
less proteid and fat absorbed from the intestine, this appears too small 
to account for the loss in weight. There seems no reason to suppose 
that any marked change in the nitrogenous metabolism is induced by 
the cathartics, for the nitrogen in the urine is often practically unal- 
tered in amount. The only remaining explanation of the efficiency of 
these salts in obesity is that they increase the oxidation of the fats of the 
body, presumably by altering the movements of the body fluids. This, 
however, is only a surmise which as yet is unsupported by known facts. 

When purgation follows the administration of a saline cathartic, 
the most of the salt escapes in the faeces, never having been absorbed 
at all. When the salt fails to purge, however, and is absorbed, it 
undergoes the usual exchanges in the tissues and is excreted by the 
urine. There is no reason to suppose that any of it appears again in 
the stomach or intestine. 

The Sulphates seem to pass through the tissues without injuring them, 
and but little effect is observed from injecting considerable quantities into 
the blood. When the sulphate ion is combined with a poisonous base such 
as potassium or magnesium, the injection is of course followed by character- 
istic symptoms, but the anion seems to be comparatively harmless. It is 
said that when G-lauber's salt (Na 2 S0 4 ) is given by the mouth, the basic por- 
tion is excreted much more quickly than the acid, so that the urine may be 
rendered alkaline temporarily. On the other hand when sulphate of mag- 
nesium is administered, the sulphate is absorbed and appears in the urine in 
large quantity, while the magnesium remains unabsorbed for the most part. 

The Phosphates are also very inactive after absorption. Gamgee found 
the orthophosphate quite harmless, while the metaphosphates and pyrophos- 
phates are poisonous, more especially the last. When injected subcutane- 
ously or intravenously, the pyrophosphate of soda induces fatty degenera- 
tion of the liver and heart like phosphorus, but it seems to be harmless when 
administered by the stomach, in which it is perhaps oxidized to the ortho- 
phosphate. 

The Citrates are rapidly oxidized in the tissues to carbonates, and only 
traces of the unchanged salt escape in the urine. The urine may thus be 
rendered alkaline by the administration of the citrates, especially in small 
quantities which are insufficient to induce purgation (see hydrates and car- 
bonates of the alkalies, page 549). The Tartrates are more slowly oxidized, 
and a considerable quantity is excreted in the urine unchanged. 1 Injected 
into the blood directly, the citrates and tartrates seem to act as heart poisons, 
but very little is known in regard to this point. 

The Magnesium Salts first accelerate and then weaken and paralyze the 
heart and depress the central nervous system, when they are injected into 

1 Lsevo-rotary tartaric acid is much more readily oxidized in the body than dextro- 
rotary. (Brion, Ztschr. f. phys. Chem., xxv., p. 283.) 



540 INORGANIC SALTS, ACIDS AND BASES. 



. 



the blood, but induce no symptoms when they are absorbed from the intei 
tine, as they are probably rapidly excreted by the kidneys. The magnesium 
of the urine is certainly increased by the administration of the salts by the 
mouth, especially if they fail to purge, but it is possible that some of the mag- 
nesium is excreted by the bowel, and it has been recently suggested that it 
may appear in the milk. In the frog the salts of magnesium are said to 
paralyze the striated muscles in the same way as those of potassium, but 
no such effect is induced in mammals even by intravenous injection, the 
animal dying from the action on the heart and nervous system before the 
muscular action is elicited. 

The oxide and carbonate of magnesium differ from the other saline 
cathartics in being very insoluble and in possessing an alkaline reac- 
tion. Part of that ingested is formed into magnesium chloride in the 
stomach, however, and the carbonic acid present in the intestine may 
dissolve part by forming the bicarbonate. Their alkalinity serves to 
remedy any excessive acidity of the stomach or intestine, while at the 
same time they are mildly cathartic. (See page 545.) The prolonged 
use of large quantities of magnesia has in some cases led to the forma- 
tion of large concretions in the bowel, resulting in obstruction, 

Preparations. 

Sodii Sulphas (U. S. P., B. P.), Glauber's salt (Na 2 S0 4 , 10H 2 O), soluble 
in about 3 parts of cold water, 2-30 G. (30 grs.-l oz.). 

Magnesii Sulphas (U. S. P., B. P.), Epsom salts (MgS0 4 ,7H 2 0), soluble 
in 1| parts of cold water, 2-30 G. (30 grs.-l oz.). 

Potassii Sulphas (IT. S. P., B. P.), 1-4 G. (15-60 grs.). 

These are crystalline salts with a harsh, bitter taste. 

Sodii Phosphas (IT. S. P., B. P.) (Na 2 HP0 4 + 12H 2 0), soluble in about 6 
parts of cold water, 1-30 G. (15 grs.-l oz.). 

Sodii Pyrophosphas (IT. S. P.) (Na 4 P 2 0. + 10H 2 O), 1-20 G. (15-300 grs.). 

These are crystalline salts with a cool, saline taste. 

Potassii B itartras (IT . S. P.), Potassii Tartras Acidus (B. P.), cream of tartar 
(KHC 4 H 4 6 ), 1-4 G. (15-60 grs.). 

Potassii et Sodii Tartras (U. S. P.), Soda Tartarata (B. P.), Rochelle 
salt (KNaC 4 H 4 6 + 4H z O), soluble in 1.4 parts of cold water, 8-16 G. (120- 
240 grs.). 

Potassii Tartras (B. P.) ((CHOH) 2 (COOK) 2 H 2 0), 30-240 grs. 

Potassii Citras (U. S. P., B. P.) (C 3 H 4 OH(COOK) 3 ), 1-3 G. (15-45 grs.). 

Lithii Citras (IT. S. P., B. P.) <C 3 H 4 OH(COOLi) 3 4H 2 0), 0.3-0.6 G. (5- 
10 grs.). 

These five form crystalline salts with a cool saline or, in the case of the 
bitartrate, acidulous taste. They are all very soluble in water except the 
bitartrate. The citrates are not purgative in the dose given. 

Magnesia (U. S. P.), Magnesia Levis (B. P.), light or calcined magnesia 
<MgO). 

Magnesia Ponderosa (U. S. P.. B. P.), heavy magnesia (MgO). 

Magnesii Carbonas (IT. S. P.) ((MgC0 3 ) 4 Mg(OH) 9 + 5H 2 0). 

Magnesii Carbonas Levis (B. P.) ' ) ( o m „ co x tywOEH 4H O) 

Magnesii Carbonas Ponderosa (B. P.) | W M S LO s)> Mg(U±i) 2 , 4±i 2 u;. 

These all form white amorphous powders with an earthy, not saline, taste. 
They are insoluble in water, but the carbonate is dissolved by excess of car- 
bonic acid. 0.3-4 G. (5-60 grs. V 

Liquor Magnesii Carbonatis (B. P.), fluid magnesia, contains 2 per cent, 
of carbonate of magnesia dissolved by the presence of carbonic acid. 1-2 
fl. oz. 



SALINE CATHARTICS. 541 

Effervescing Preparations. 

Pulvis Effekvescens Compositus (U. S. P.), Pulvis Sod.e Tartarat^i 
Effervescens (B. P.), Seidlitz powder. 

This powder is made up in two papers, of which the blue one contains a 
mixture of 3 parts of Rochelle salt and one part of sodium bicarbonate, in all 
10.4 G. (160 grs.), while the white paper contains 2.25 G. (38 grs. B. P.) of 
tartaric acid. When the powders are dissolved separately in water and the 
solutions mixed, the tartaric acid acting on the bicarbonate releases carbonic 
acid with effervescence. 

Magnesii Citras Effervescens (U. S. P.) is a dry mixture of carbonate of 
magnesium, bicarbonate of soda, citric acid and sugar. When it is mixed 
with water the citric acid acts on the carbonates and causes effervescence. 
1-3 teaspoonfuls. 

Liquor Magnesii Citratis (U. S. P.) is a solution of magnesium citrate with 
excess of citric acid to which potassium bicarbonate is added. The whole is 
bottled tightly and effervesces when the cork is removed. 150-400 c.c. 
(5-12 fl oz.). 

Lithii Citras Effervescens (IT. S. P., B. P.), a mixture of lithium carbonate 
or citrate with sodium bicarbonate, and citric acid (and tartaric acid, B. P.). 
4-8 G. (60-120 grs.). 

Magnesii Sulphas Effervescens (B. P.) is a mixture of Epsom salts, sodium 
bicarbonate, tartaric and citric acids, which effervesces when mixed with 
water. 60-240 grs. for repeated administration ; for a single administration 
J-l oz. 

Soda Sulphas Effervescens (B. P.), a similar mixture containing the sul- 
phate of soda instead of that of magnesia. 60-120 grs. for repeated admin- 
istration ; for a single administration J-J oz. 

Sodii Phosphas Effervescens (B. P.), similar to the above but containing the 
phosphate in place of the sulphate. Dose as for the effervescent sulphate. 

Sodii Citrotartras Effervescens (B. P.), a mixture of sodium bicarbonate 
with tartaric and citric acids. It is not purgative in the dose advised in the 
B. P. 60-120 grs. 

Many other effervescent mixtures are used instead of the official ones — 
among them the tartrates and citrates of the alkalies, the acetate of mag- 
nesium, etc. 

The sulphates of sodium and of magnesium, the tartrates of sodium and 
potassium and the phosphate of soda are given in solution, the last often in 
milk. Unless under special conditions the salts ought not to be in greater 
concentration than 5-10 per cent. Magnesia and magnesium carbonate are 
administered in powder, sweetened if necessary. The effervescent prepara- 
tions are always to be taken in solution in about a tumbler of water ; in 
some instances in which this was not understood, severe distention of the 
stomach w r ith alarming symptoms have arisen from the carbonic acid being 
freed in the stomach. The effervescent preparations ought to be kept dry, 
and the solution of magnesium citrate has to be kept tightly corked. 

Very often the natural mineral waters are used instead of the pharmaco- 
pceial preparations, the best known purgatives among these being the Hun- 
yadi-Janos water and Carlsbad water, which contain the sulphates of sodium 
and magnesium. " Carlsbad salts" are obtained by the evaporation of the 
waters, but are very often artificial imitations. Many other springs have 
the same effects, and a widespread belief exists that the natural waters are 
" more efficient " or u less depressant " or have some mystical virtues that 
are not shared in by the artificial salts, but this belief does not seem to have 
any real basis, and is probably a survival of the old religious belief in the 
healing properties of springs. 

In the natural waters the purgative salts are always accompanied by other 
less active ones, such as the chlorides of sodium, calcium, etc. 

The sulphovinate of sodium (NaC 2 H.S0 4 ) has been advised as an aperient, 
but is much weaker than the others, though it has a more pleasant taste. 



•542 IN011GANIC SALTS, ACIDS AND BASKS. 

It is very liable to decompose with the formation of sulphate of soda, and 
perhaps much of its action may be due to the presence of the latter. 

Therapeutic Uses. — The saline cathartics are very largely used to 
relieve constipation. Habitual constipation seems to be caused by 
insufficient peristalsis, and the slow passage of the contents through the 
intestines allows of a more complete absorption than usual, this in 
turn rendering the faeces hard and dry and difficult to move onwards. 
The saline cathartics increase the fluidity of the intestinal contents, and 
thus facilitate their expulsion, and this is probably the only effect they 
have when taken in small quantities, and especially in dilute solution 
as in the natural mineral waters. In larger quantities, however, more 
water is retained in the bowel, and the weight and distention cause 
peristalsis, while in sufficient quantity they draw fluid from the blood 
and cause profuse watery discharges. When a very complete evac- 
uation is desired, the saline cathartics may be given along with some 
of the vegetable purgatives. Such mixtures are the official Black 
Draught (see Senna) and the compound powder of Jalap. The saline 
cathartics act much more rapidly than the vegetable purgatives, and a 
common method of combining their effects is to give the latter in the 
evening and the saline the following morning. 

The chronic constipation due to sedentary habits is much benefited 
by the saline cathartics, more especially by dilute solutions taken be- 
fore breakfast. The sulphates and tartrates are harsh and unpleasant 
to the taste, and the natural waters are often preferred, or one of the 
effervescent preparations may be used in those cases. 

The sulphates and tartrates are more frequently used where a single 
large dose has to be prescribed in order to empty the bowel, but here 
also the Seidlitz powder may be advised instead, as being more agree- 
able to the taste. These cathartics were at one time used in fever, 
partly from a theory that they reduced the temperature ; they are cer- 
tainly less liable to cause pain and griping than the vegetable purga- 
tives, and thus tend to disturb the patient less. 

The sodium phosphate is often prescribed for children, either as a 
powder to be given in jelly, or in solution in milk or other food, which 
completely hides its taste. 

The saline cathartics are used to lessen intestinal putrefaction, and 
are sometimes very efficient, though they do not act through any an- 
tiseptic power, but simply by removing the putrefying mass. The 
phosphate of soda has been especially recommended in some forms of 
diarrhoea in children. 

The saline cathartics are administered to remove accumulations of 
fluid in the body arising from cardiac or renal insufficiency, or from 
an old effusion. For this purpose the sulphate of magnesium is used 
in a large dose, dissolved in as little water as possible ; if purgation does 
not follow in 1—3 hours, an enema may be necessary, or the saline may 
be given along with a vegetable purgative. This form of treatment 
was very popular at one time, but is liable to weaken and depress the 
patient, and is specially contraindicated therefore in asthenic conditions. 






SALINE CATHARTICS. 543 

Other methods of removing accumulations of fluid are by the use of 
diuretics (see caffeine, theobromine, page 245), diaphoretics (see pilo- 
carpine, page 315), or by cardiac remedies (digitalis, page 440). 

As diuretics the saline cathartics are inferior to other salts, such as 
the acetates or nitrates. Large quantities of dilute solutions of the 
purgative salts are of value in the treatment of some forms of obesity, 
the mineral waters being generally prescribed for this purpose, or the 
patient being sent to drink them at their source. 

Magnesia and magnesium carbonate are less liable to purge than 
the soluble salts, and are specially indicated in hyperacidity of the 
stomach or in acid putrefaction in the bowel. They cause less irrita- 
tion than the carbonates of the alkalies because of their insolubility, 
and at the same time have the advantage of acting as mild purgatives, 
while the lime preparations which are insoluble, tend to induce con- 
stipation. The magnesia preparations may be used also in diarrhoea 
as antacids, as they have no irritant action on the bowel. Freshly 
prepared magnesia is recommended in arsenic poisoning to form an in- 
soluble precipitate in the stomach, and in poisoning with acids it is 
also of value when it can be obtained readily. In both cases it is to 
be given in large quantities. 

The phosphate of soda has been given in various bone diseases, as in 
osteomalacia and rickets, this treatment being founded on the belief that 
the softening of the bones is due to the lack of phosphates in the food, but 
there is no reason to suppose that this idea is correct, and the treatment 
is not attended with success. In cases of exophthalmic goitre the phosphate 
has been recommended, but no explanation has been given of its action here, 
and some question exists as to whether it is really of value. 1 It has also 
been recommended in the uric acid diathesis. The phosphates have been 
supposed to be of benefit in nervous diseases, on the theory that these were 
due to the insufficiency of phosphorus in the brain, and glycerophosphates 
have been introduced for the same reason, but both theory and practice have 
proved to be erroneous, for the animal organism is unable to build up proteid 
combinations from their inorganic constituents. The use of sulphate of 
sodium in phenol poisoning, which was at one time recommended, has been 
shown to be quite without effect on the progress of the intoxication. (See 
Carbolic Acid, page 404.) 

The ferrocyanide of potassium has been advised in irritant poisoning with 
iron and copper salts, with the hope that the insoluble ferrocyanides would 
be formed ; a better treatment, however, is washing out the stomach, and 
the greater part of these salts is removed by vomiting in any case. 

Bibliography. 

The literature of saline cathartics up to 1884 is discussed by Hay. See also Vegetable 
purgatives, p. 110. 

Hay. Saline cathartics, Journ. of Anat. andPhys., xvi. and xvii. ; also in mono- 
graph," Edinburgh, 1884. 

London. Zts. f. klin. Med., xiii., p. 48. 

Dapper. Ibid., xxx., p. 371. Arch. f. Verdauungskrank., iii., p. 1. 

Jacoby. Berl. klin. Woch., 1897 ; p. 248. 

Heidenhain. Pfliiger's Arch., lvi., p. 579. 

1 A curious antagonism is said to exist between iodide of soda and phosphate of soda 
in regard to the cardiac nerves. See Barbera, Pfliiger's Arch., lxviii., p. 434 and 
Cyon, ibid., lxx., p. 126. 



544 INORGANIC SALTS, ACIDS AND BASES. 

KovesL Centralbl. f. Physiol., 1897, p. 553. 
Hamburger. Arch. f. Anat. u. Phvs., 1896, p. 428. 
libber. Pfliiger's Arch., lxx., p. 624. 
Flemming. Inaug. Diss., Dorpat. 1893. 

Wallace and Cushny. Am. Journ. of Physiol., i., p. 411. Pfliiger's Arch., lxxvii., 
p. 202. 

Gamgee, Priestley and Larmuth. Journ. of Anat. andPhys., xi., p. 255. (Phosphates. ) 
Swiatecki. Ztschr. f. phys. Chem., xv., p. 49. 

XIV. HYDRATES AND CARBONATES OF THE ALKALIES. 

The hydrates and carbonates of potassium, sodium and lithium owe 
their pharmacological action entirely to the non-metallic ion, which 
is so much more powerful than the metal that the latter may be dis- 
counted. In the hydrates the active constituent, then, is — HO. 
The carbonates and bicarbonates dissociate into K- or Na- ions and 
— C0 3 , but the latter rapidly combines with the hydrogen of the water 
and thus frees — OH, so that the final effect is the same as if a hydrate 
had been administered, except that the carbonates are less rapidly dis- 
sociated than the hydrates, and, less — OH being formed, are less violent 
in their .action. This hydroxyl ion, then, is what induces the alkaline 
reaction of the solutions and their pharmacological effect, the metallic 
ion only serving as a means of applying the hydroxyl ion, but not 
affecting the pharmacological action. In other words the alkalinity 
(hydroxyl ion) of the hydrates and carbonates determines their action ; 
the metal has no practical importance. 

It is therefore erroneous to take the hydrates and carbonates as typifying 
the action of potassium or sodium, for in these the metallic action is much 
less distinct than in the chlorides, the CI ion being practically inert, while 
the hydroxyl is exceedingly poisonous. 

It may be remarked in passing that the importance of the reaction be- 
tween alkalies and acids lies not in the combination of the metal with the 
anion of the acid, but in the combination of the powerful hydroxyl ion with 
the hydrogen ion of the acid. In the effects of potassic hydrate in the 
stomach, the main importance is to be attached not to the potassic chloride 
formed but to the water (K — HO -f H — CI = K — CI + H 2 0), for the potas- 
sium and chloride ions remain unchanged by the operation while the hydroxyl 
and the hydrogen ions disappear. 

Action. — The pharmacological action of this group is due to their 
powers of neutralizing acids and of dissolving proteids and changing 
them to alkali-proteids, and in a less degree to their saponifying fats. 
They have in addition the ordinary salt-action, and in concentrated 
solutions withdraw fluid from the tissues. 

The solution of proteids by the alkalies and the characters of the 
compounds thus formed outside the body are well known and need not 
be entered into here. The same solvent action is observed in the living 
tissues whenever the hydrates and carbonates come in contact with 
them in sufficient concentration. The hydrates are, of course, much 
more powerful solvents than the carbonates, and these than the bicar- 
bonates. In very dilute solutions this solvent action is exercised only 
on the superficial tissues, but when stronger solutions are used, or 
when even weak solutions remain long in contact with the tissues, 



HYDRATES AND CARBONATES OF THE ALKALIES. 545 

they tend to penetrate more deeply and cause widespread destruction 
or corrosion. These bodies form soluble compounds with the proteids 
and are only slowly neutralized by the tissues, so that no such barrier 
is raised against their penetration as is met by some other corrosives. 

Applied to the Skin weak solutions dissolve the superficial layer of 
horny matter and the oily secretions of the glands, and thus cleanse 
the surface more thoroughly than water or solutions of neutral salts. 
When applied for some time, they penetrate more deeply and cause 
some slight irritation and redness. Concentrated solutions dissolve 
the skin and cause necrosis of the deeper tissues, generally covered 
by a semitransparent crust, which falls off in the course of a few 
days, leaving an ulcer. The solutions of the carbonates are much less 
corrosive than those of the hydrates, and induce actual lesion of the 
skin only under exceptional circumstances, such as very prolonged 
application. 

In the Mouth the hydrates and carbonates have a characteristic 
" alkaline " taste, and dissolve the superficial layers of the lining mem- 
brane and the mucus of the secretions. The lips, tongue, and gums 
assume a bright red color from the irritation and feel soapy to the 
touch. Concentrated solutions may cause deep corrosion, as in the 
skin, while very weak solutions have no effect except the characteristic 
taste and a reflex flow of saliva. The corrosion caused by strong solu- 
tions extends to the throat and oesophagus, and may either prove im- 
mediately fatal or may give rise to cicatrices subsequently. 

The effect of the hydrates and carbonates in the Stomach has been 
much disputed, and even now it is impossible to explain some of the 
therapeutic results. Small quantities are undoubtedly neutralized by 
the hydrochloric acid of the gastric juice and act no longer from their 
alkalinity, but merely from their effects as salts, if at all. Larger 
quantities render the contents of the stomach neutral or alkaline and 
thus prevent gastric digestion. Very concentrated solutions corrode 
the walls of the stomach and may prove immediately fatal from caus- 
ing perforation into the peritoneal cavity, while if the corrosion is not 
so severe, and the patient recovers from the shock and collapse, gastric 
ulcer and cicatrices may result. 

It is very frequently stated that alkalies and alkaline carbonates in- 
duce a more rapid secretion of the gastric juice. In fact, some writers 
go so far as to assert that it is impossible to render the contents of the 
stomach alkaline except by the use of poisonous doses, because the 
gastric juice is so rapidly augmented by the alkalies. This belief 
seems to be founded on the old aphorism contraria conirariis stimulan- 
tur, which proves to have no greater basis in fact than other similar 
dogmas. It has been demonstrated experimentally in dogs that alka- 
line carbonates, whether given by the mouth or injected into the 
stomach through a gastric fistula, do not influence the amount of the 
gastric secretion, and Reichmann has recently shown that in man dis- 
tilled water increases the free acid and the chlorides of the stomach 
contents as much as an equal amount of an alkaline solution. The 
35 



546 INORGANIC SALTS, ACIDS AND BASES. 

only satisfactory examinations of the question, therefore, show that the 
alkalies have no effect whatsoever on the activity of the secretory 
glands of the stomach. On the other hand, they may affect the juice 
already secreted by making it neutral or even alkaline, and may thus 
render it entirely useless for digestion and disinfection. Of course in 
hyperacidity of the stomach, the alkalies may be of benefit by lessen- 
ing the amount of free acid present. 

Dilute solutions of the alkalies may act as slight irritants to the 
stomach wall and thus improve its circulation, and lessen pain, eruc- 
tation and distention, very much in the same way as other slight gas- 
tric irritants, such as the volatile oils. In the case of the carbonates 
and bicarbonates, this carminative action may be strengthened by the 
carbonic acid liberated by the hydrochloric acid. In addition, they 
tend to render the mucus less tenacious, or may dissolve it completely, 
and thus improve the condition of the stomach. Nothing is known as 
to their effects on the movements of the stomach, or on its power of 
absorption, but if carbonic acid be liberated, it tends to increase the 
movements to some extent. 

In the small Intestine the alkalies have been shown to have an in- 
direct effect, through their diminishing the acidity of the gastric juice. 
The secretion of the pancreas is normally stimulated by the passage of 
an acid fluid through the pylorus, and if the acidity of this fluid be 
reduced by the administration of alkalies, a much smaller quantity of 
pancreatic juice is thrown into the intestine. This may again render 
the digestion less complete, although the greater alkalinity of the 
intestinal contents tends to increase the efficiency of the pancreatic 
juice already secreted. On the other hand, in cases of hyperacidity of 
the stomach, the administration of alkalies may render the contents of 
the intestine less irritant, and thus tend to allay catarrh. 

The alkalies administered in medicinal doses seem to have no effect 
on the intestinal putrefaction, for the double sulphates of the urine 
remain unchanged in amount. Kast states that very large quantities 
(15 G., J oz.) increase the putrefaction, probably through neutralizing 
the disinfectant gastric juice. 

The alkalies have been believed to have some special action on the 
Secretion of Bile ; thus, it has been supposed that they rendered the 
bile more alkaline and tended to dissolve the mucus contained in it, 
that they prevented the deposition of, and even dissolved gall-stones, 
or that they increased the secretion of bile and thus swept them out of 
the gall-bladder. All of those theories have been overthrown by the 
investigations of Stadelmann and his pupils, who have shown that 
alkaline salts do not increase the secretion of bile, are not excreted in 
it, and do not cause any change in its reaction. Any effect which the 
alkaline carbonates or hydrates may possess in hepatic diseases would 
therefore seem due to their effects in the duodenum. 

The prolonged administration of very large doses of the alkaline car- 
bonates and bicarbonates causes chronic gastro-enteritis in animals, and 
is said to have proved fatal to them in some instances. 



HYDRATES AND CARBONATES OF THE ALKALIES. 547 

The hydrates are probably Absorbed in combination with proteids or 
as carbonates. Both hydrates and carbonates disappear rapidly from 
the stomach and intestine, although the bicarbonate of soda is some- 
times credited with some laxative action • this may not, however, be 
due to the same causes as in the case of the saline cathartics. The 
absorption of these bodies leads to an increase in the alkalinity of the 
blood and tissues. Even when the alkali administered has been neu- 
tralized by the gastric juice, the body is rendered more alkaline, be- 
cause a certain amount of the carbonate of the blood and tissues is 
spared, which would normally have been used to neutralize the hydro- 
chloric acid before it could be reabsorbed. This condition of aug- 
mented alkalinity can only last a short time, however, as the excretory 
glands at once proceed to remove the excess. But this transient in- 
crease in the alkalinity of the tissues has been supposed to influence 
the Metabolism very considerably. It is found that outside the body 
certain bodies undergo oxidation much sooner in alkaline solution 
than when neutral ; the example most frequently cited is pyrogallol, 
which combines with oxygen much more rapidly in the presence of 
alkalies. From this it has been surmised that an increase in the alka- 
linity of the fluids of the body must be followed by an acceleration of 
the metabolism. A large number of researches made on man and ani- 
mals in regard to this point have given varying results, but tend on 
the whole to show that the alkalies have less effect on the tissue- 
change than was formerly believed. The investigators of the subject 
have generally confined their attention to the effects of alkalies on the 
products of metabolism excreted in the urine, and have found the total 
nitrogen excreted to be unchanged in a considerable number of in- 
stances, to be slightly increased in others, and to be diminished in a 
few individuals. Even in those cases in which an increase is observed 
in the nitrogen of the urine, it does not always indicate an increase in 
the nitrogenous metabolism, for the urine is often increased consider- 
ably and it is evident that the interchange of the fluids of the tissues 
and blood is augmented ; so that the increased nitrogen of the urine is 
accounted for by the tissues being more thoroughly flushed out than 
usual by the alkalies, which act in the same way as the neutral salts. 
(See page 494.) The effect of the alkalies on the total nitrogen ex- 
cretion seems to vary considerably with the individual, and in one and 
the same person different effects have been noted from two salts which 
exist in the blood in the same form. 

Although the total nitrogen may be little affected by the administra- 
tion of the alkalies, the form in which it is combined in the urine and 
in the blood may be changed. The ammonia of the urine is often 
diminished in amount, while the urea excretion is correspondingly aug- 
mented. This is especially marked in cases in which excess of acid is 
formed in the tissues or absorbed in any way, and is explained by the 
fact that this acid is ordinarily neutralized by the formation of ammo- 
nia in the tissues (see Acids). When, however, fixed alkali is present 
in sufficient amount, as when the carbonates are given, the nitrogen 



548 INORGANIC SALTS, ACIDS AND BASES. 

which would otherwise have been excreted as ammonium salts, is 
formed into urea. 

The Uric Acid Excretion under the alkalies has been the subject of 
numerous researches, but in the great majority of these very imperfect 
methods of estimation have been used. In the few cases in which 
satisfactory methods have been employed, the results have been diver- 
gent, the uric acid being sometimes decreased and sometimes increased 
by the alkalies. 1 This has been explained by an increase or decrease 
in the oxidation having occurred, it being tacitly assumed that the 
amount of uric acid formed remained unchanged, but that in the one 
case a greater amount than usual was destroyed in the tissues, in the 
other a smaller amount than usual. It seems not unlikely, however, 
that the true explanation is that the local action of the alkali on the 
alimentary tract sometimes causes an increased formation and destruc- 
tion of the leucocytes and thus increases the uric acid. It is true that 
Pohl could not detect any increase in the leucocytes of the blood when 
bicarbonate of soda was exhibited, but no investigations have been 
carried out in which the leucocytes and the uric acid were both esti- 
mated under the alkalies. 

As regards the Oxidation in the Tissues, one observer found the oxy- 
gen absorbed and the carbonic acid excreted by the lungs increased by 
the alkalies, while another could detect no change. Another method 
of estimating the activity of the oxidation in the tissues has been used 
by Taniguti and Jawein, who both found that in man the neutral sul- 
phur of the urine is increased by the alkalies at the expense of the 
acid sulphates ; they interpret this as indicating a diminution of the 
oxidation of the tissues. On the other hand, Heffter and Harnack, 
using the same method, came to the conclusion that the oxidation in 
the tissues of the dog was increased by the alkalies, and this accords 
with Munk's observation that a diminution of the alkalinity of the 
blood of the horse lessened the oxidation of phenol. 

The only conclusion which seems admissible from these laborious 
investigations, is that the tissue waste is but little affected in amount 
by the increased alkalinity of the blood, and the slight changes ob- 
served may vary not only in different species, but in different individ- 
uals, and even in the same individual at different times. The cause 
of this individual variation may be differences in the amount of acid 
formed in the tissues, but may also be differences in the local effect of 
the alkalies in the alimentary tract. 

The organism rapidly frees itself from the excess of alkali by Ex- 
creting alkaline salts. This excretion occurs chiefly in the urine, 
which becomes less acid, or even alkaline in reaction, and in the latter 
event contains bicarbonate of potash or soda. As a general rule, the 
urine soon regains its acidity, but when fairly large doses are given 
repeatedly, its action may be kept alkaline constantly. This is almost 
always accomplished in man by the administration of about 10-15 G. 

1 Stadelmann and his pupils found that very large doses lessen the uric acid in the 
urine, while smaller ones had no effect on it. 



HYDRATES AND CARBONATES OF THE ALKALIES 549 

(160-240 grs.) of sodium carbonate in 24 hours, but some persons 
require a still larger quantity, while others require much less. A tem- 
porary alkaline reaction lasting 2-3 hours may often be induced by a 
single dose of 2-3 G. The alkalies have the same effect on the excre- 
tion of the salts in the urine as the neutral salts — large doses increase 
the sodium, potassium and chlorides of the urine. 

The injection of alkaline carbonates into the blood induces a more active 
secretion from the bronchial mucous membrane, according to Calvert, while 
Rossbach found it to have the opposite effect. It is questionable whether 
the alkali is excreted here. 

The blood of rabbits treated with alkalies is said to be more strongly ger- 
micidal than usual, and these animals show greater resistance to infection 
with anthrax bacilli. These effects are not due to the increased alkalinity 
of the blood directly, for serum is not rendered more bactericidal when 
alkali is added to it in test-tube experiments. 

When dilute alkaline solutions are applied to Isolated Organs, they gen- 
erally increase their activity for a time, but subsequently weaken it, while 
strong solutions are immediately poisonous. Thus the ciliary movement of 
epithelium is accelerated by dilute alkalies, the sodium salts acting more 
strongly than the potassium because of the poisonous K-ion of the latter. 
The frog's heart also contracts longer and more strongly when it is perfused 
by a chloride of sodium solution rendered alkaline by carbonate of soda 
than when the solution is neutral. Somewhat stronger solutions increase 
its tonus and eventually cause systolic standstill. The arteries are con- 
tracted in the same way by contact with alkaline solutions, and are dilated 
when acids are perfused through them. Some of the secretions have also 
been found to be increased by the presence of alkalies, thus the glands of 
the frog's skin are stimulated by very dilute alkaline solutions. Loeb has 
recently observed that the presence of the — OH ion causes frog's muscle 
to absorb considerable quantities of water from a dilute salt solution, while 
on the other hand Hamburger states that the addition of small quantities of 
alkalies to the drawn blood reduces the size of the blood cells. Zoethout 
states that some unicellular organisms prove much more resistant to the 
effects of the withdrawal of oxygen when they are placed in a slightly alka- 
line medium, and suggests as an explanation that the alkali antagonizes 
some poison formed during asphyxia. 

Strong alkaline solutions destroy all living tissues with which they come 
in contact. 

Preparations. 

Potassa (U. S. P.), Potassa Caustica (B. P.) (KOH), potassium hydrate, 
caustic potash — dry white pencils or fused masses, deliquescent in the air 
and very caustic. 

Potassa cum Calce (IT. S. P.), Vienna paste, equal parts of caustic potash 
and unslaked lime — a grayish powder. 

Soda (U. S. P.) (NaOH), sodium hydrate or hydroxide, caustic soda, white 
translucent pencils, deliquescent in the air, and very caustic. 

Liquor Potassse (U. S. P., B. P.), solution of potassium hydrate, about five 
per cent., 0.6-2 c.c. (10-30 mins.), to be well diluted. 

Liquor Sodfe (U. S. P.), a solution of sodium hydrate in water, about five 
percent., 1-4 c.c. (15-60 mins.), well diluted. 

Liquor Sodii Ethylatis (B. P.), an 18 per cent, solution of sodium ethylate 
(0 2 H 5 ONa) in absolute alcohol. It should be recently prepared, when it 
forms a colorless syrupy liquid, which decomposes in the presence of water, 
and is very caustic. 

Potassii Carbonas (U. S. P., B. P.) (K,C0 3 ), a white granular powder of 
alkaline reaction, soluble in one part of water. 0.5-3 G. (5-30 grs.); 



550 INORGANIC SALTS, ACIDS AND BASKS. 

Sodii Carbonas (U. S. P., B. P.) (Na 2 C0 3 -f 10H 2 O), colorless crystals 
with an alkaline reaction and taste, soluble in about one part of water. 
0.3-2 G. (5-30 grs.). 

Sodii Carbonas Exsiccatus (U. S. P., B. P.), sodium carbonate deprived of 
most of its water of crystallization, a loose, white powder resembling the 
ordinary carbonate in its reactions and solubility. 0.3-1 G. (5-15 grs.). 

Potassii Bicarbonas (U. S. P., B. P.) (KHCO,), colorless, transparent 
crystals with a saline, slightly alkaline taste and soluble in three parts of 
water. 0.5-2 G. (10-30 grs.). 

Sodii Bicarbonas (U. S. P., B. P.) (NaHCO s ), a white, opaque powder, 
with a cool, alkaline taste, soluble in 11 parts of water at 15° C. 0.3-2 G. 
(5-30 grs.). 

Trochisci Sodii Bicarbonatis (U. S. P., B. P.). 

Sodium bicarbonate is contained in the Mistura Rhei et Sodse (U. S. P.). 

Lithii Carbonas (U. S. P., B. P.) (Li 2 C0 3 ), a light, white powder with an 
alkaline taste, soluble in 80 parts of water, but more soluble in carbonic 
acid water. 0.2-0.6 G. (3-10 grs.). 

The preparations of magnesia and magnesium carbonate (see pp. 540-541) 
are prescribed more as antacids than as cathartics, and might be included in 
this list. 

Numerous alkaline mineral waters are used instead of the pharmacopoeial 
preparations, but as a general rule they contain only very small quantities 
of the carbonates, and perhaps act more through the large amount of water 
than through their alkaline reaction. 

Therapeutic Uses. — The caustic alkalies are used Externally to a 
limited extent to remove growths such as warts from the skin. For 
this purpose the potash pencils are employed, but they are very de- 
liquescent and it is therefore difficult to limit their action to one spot, 
and to the superficial tissues. When the desired extent of cauteriza- 
tion has been obtained, the part should be washed with water, or with 
vinegar or some other dilute acid. The Vienna paste (U. S. P.) is 
somewhat milder and slower in its action and is more easily controlled. 
The solution of sodium ethylate (B. P.) is said to be less painful than 
caustic potash. The carbonates are also used externally to some ex- 
tent, chiefly in baths, which they render more irritant to the skin, and 
in which they tend to soften and remove the superficial horny layers 
of the epithelium more than ordinary water or solutions of the neutral 
salts. The carbonates are also applied in strong solution or as a paste 
in itching skin diseases, and often give relief. 

Internally the alkaline carbonates and more rarely the solutions of 
the hydrates are used for their effect on the stomach, and in cases of 
hyperacidity relieve the pain and eructation almost instantly. Even 
where no excessive acidity exists, the alkalies are often beneficial in 
small quantities, removing the distension and discomfort without 
apparently altering the digestion to any marked extent. The bicar- 
bonate of potash is more frequently used for this purpose than the 
others, and the solutions of the caustic alkalies are comparatively rarely 
employed. Whatever preparation be used, it ought to be well diluted 
to avoid the irritant action on the stomach wall. Instead of these 
alkalies the carbonate and oxide of magnesium may be employed in 
powder, and possesses the advantage of not causing any irritation and 






HYDRATES AND CARBONATES OF THE ALKALIES. 551 

at the same time have some aperient action. In cases of hyperacidity 
the alkalies (antacids) are often given after meals, while when the 
secretion does not seem to contain an excessive amount of acid they are 
advised before meals, and may then be combined with other stomachics, 
such as bitters or volatile oils. 

The alkalies are also administered for their effects after absorption, 
and here the bicarbonate of potash is most frequently prescribed, 
while the hydrate solutions are rarely used. 1 Diabetes was formerly 
treated in this way, in the hope that the oxidation in the tissues would 
be increased, but there is little reason to suppose that the alkalies have 
any such effect on the metabolism, and it is now generally accepted 
that diabetes is not due to a general inability of the tissues to oxidize. 
Experience too has shown that the glycosuria is not lessened appreci- 
ably by the use of the alkalies. When, however, diabetes induces an 
increased acid formation in the tissues, as is almost invariably the case 
in its later stages, the alkalies are of undoubted benefit in neutraliz- 
ing the oxybutyric acid formed and thus economizing the alkalies of 
the blood. In diabetic coma, temporary improvement may very often 
be attained by the use of large doses of alkalies. 

In gout, rheumatism, and the " uric acid diathesis " generally, the 
alkalies have been used very extensively, partly in the hope that the 
supposed increased combustion in the tissues would destroy a larger 
amount of the uric acid, and partly with the idea that the uric acid 
being neutralized in the tissues, would be excreted more easily and 
would have less tendency to be deposited. There are some grounds for 
believing that the alkaline carbonates are of benefit in gout and rheu- 
matism, but neither of these theories seems sufficient to explain their 
effects, for no increase in the oxidation has been shown to occur, and 
on the other hand the uric acid is not believed to exist in either the 
blood or the urine in such simple combinations as the urates. In the 
present position of the uric acid question and of the pathology of 
these diseases, however, it is futile to attempt to explain their thera- 
peutics, though it may be surmised that the alkalies may influence the 
formation of the uric acid rather than its excretion. The sodium and 
potassium salts have been used very largely, and the lithium carbonate 
has been advised on the ground that lithium urate is about four times 
as soluble as sodium urate. Lithium has also been administered in 
the form of the benzoate and salicylate in these diseases, in order to 
combine the solvent action of the base with the effects of these acids, 
but, as in so many other similar attempts, one of the chief factors in 
the action has been lost sight of; much too small quantities of the 
lithium compounds have been given to affect the reaction of the blood, 
and besides the salicylate and benzoate do not alter it at all, as they 
are neutral salts. These lithium compounds therefore seem to be 
superfluous in the treatment of these diseases. More benefit is derived 
from the treatment of gout and rheumatism by the alkaline mineral 
waters than by artificial preparations, and this is especially marked 
ir The acetates, citrates, etc., may also be used for this purpose (page 554). 



552 INORGANIC SALTS, ACIDS AND BASES. 



when patients are sent to the mineral springs. The alkalinity of mos 
of the waters is very slight, and the conclusion is inevitable that the 
curative agency is not the alkalinity, but the large amount of fluid 
taken, together with the dietetio and other hygienic conditions. 

The alkaline preparations are also largely used for their effects in the 
urine. In cases of excessive acidity of the urine leading to pain and 
straining during micturition, the symptoms are relieved by these drugs 
rendering the fluid less irritating, and this relief is especially marked 
in irritable conditions of the bladder and urethra. They may also 
be of value in those cases by rendering the mucus more soluble in 
the bladder. In gravel the alkalies also give relief, and this has been 
attributed to their dissolving the uric acid in the urine, or rather to 
their keeping it in solution in the form of salts. In order to attain 
this, the urine would have to be rendered alkaline, or at least neutral, 
and relief is given by quantities of the alkalies which are quite insuffi- 
cient to do this, so that it seems more probable that the effects are due 
to their increasing the amount of the urine, and thus rendering it more 
dilute than to their actually neutralizing the uric acid. Attempts have 
even been made to dissolve calculus in the bladder or in the kidney by 
treatment with the alkalies, but there is no question that this is hope- 
less. The solution of the alkalies formed in the urine is extremely 
dilute, and in fact, except under large doses, the reaction is not even 
constantly neutral. On the other hand, even the alkaline urates are 
by no means very soluble bodies, and are formed only with difficulty 
except in strong alkaline solutions. Again, alkaline urine is very liable 
to deposit phosphates in the bladder, and thus rather to increase the 
calculus than to diminish it. Experience has shown conclusively that 
the alkaline treatment does not remove calculus, although in one or 
two cases it is stated that soft calculi broke down into fragments under 
it, from the mucus which held the fragments together being dissolved. 
The pain and irritation of calculus may be relieved to some extent, 
however, from the acidity of the urine being lessened. 

The alkaline carbonates are also prescribed in cases of jaundice and 
gall-stone, often with benefit. This is not due to their acting on the 
bile directly in all probability, for it has been shown that they do not 
affect it in the normal animal ; the improvement may rather be 
ascribed to their lessening duodenal irritation. 

The bicarbonate of potash is often added to other expectorant reme- 
dies in the treatment of bronchial catarrh and bronchitis, and is be- 
lieved to increase the secretion and render .it more fluid and more 
easily expectorated. 

The alkaline carbonates may be given as antidotes in poisoning with 
the corrosive acids, although magnesia is preferable, because it is less 
irritating to the stomach. 

In cases of Poisoning with the caustic alkalies, the treatment con- 
sists in the administration of dilute acids, of which the organic — acetic, 
citric or tartaric — are the best. The first is most readily obtained in 
the form of vinegar. No attempt should be made to pass the stomach 



, 



HYDRATES AND CARBONATES OF THE ALKALIES. 553 

tube, as it is liable to pass through the corroded wall of the oesophagus 
or stomach. General measures, such as central nervous stimulants, 
warmth, etc., may be taken. 

Bibliography. 

Reichmann. Arch. f. Verdauungskrankheiten, i., p. 44. 

Khigine. Arch, des Scienc. biologiques, iii., p. 461. 

Becker. Ibid., ii., p. 433. 

Glass. Arch. f. exp. Path. u. Pharm., xxx., p. 241. 

Salkowski u. Spilker. Virchow's Arch., cxvii., p. 570. 

Taniguti. Ibid., cxvii., p. 581. 

Horbaczewski. Monatsh. f. Chem., xii., p. 269. 

Freudberg. Virchow's Arch., cxxv., p. 566. 

Stadehnann. Einfluss der Alkalien auf den menschlichen Stoffwechsel, 1890. 

Jawein. Ztschr. f. klin. Med., xxii., p. 43. 

Hegeler. Arch. f. Hyg., xl., p. 375. 

Calvert. Journ. of Phys., xx., p. 158. 

Passalsky u. CruszewiUch. Maly's Jahresber., xxiii. (1893), p. 427. 

Harnack u. Kleine. Ztschr. f. Biol., xxxvii., p. 417. 

Zoethout. Amer. Journ. of Physiol., ii., p. 220. 

Garrey. Ibid., iii. , p. 291. 

Piperazine and Urotropine. 

Several new organic compounds have been introduced of late years as 
solvents of uric acid in the tissues and urine. The best known of these is 

prr C*,TT 

piperazine or diethylendiamine (NH<ntT 2 prx 2 >NH) ; lyeetol and lysidine 

are nearly related bodies. Urotropine is hexamethylentetramine, (CH 2 ) fi N 4 , 
and several compounds have been introduced. The latest remedy is 
quinic acid, C 7 H 12 6 , which is found in cinchona bark and in other plants ; 
its combinations with lithium citrate, urotropine and piperazine are known 
as urosin, chinotropine and sidonal. Piperazine and its allies dissolve uric 
acid readily in the test-tube, much more rapidly than lithium or borax, 
which are often prescribed for their solvent action ; it was therefore 
hoped that these bases would prevent the deposit of uric acid in the body in 
gout by forming soluble urates, which would be eliminated in the urine. 
But very little of the piperazine ingested reappears in the urine, and this 
quantity is too small to have any solvent action on the uric acid. And what 
does escape in this way is in combination with the stronger acids and not 
with the uric acid. When the kidneys are inflamed and necrosed in birds 
through the action of chromic acid, the uric acid, which would normally be 
excreted by the kidney, is deposited in various organs, but this does not 
occur except in the kidney if piperazine is administered. This has been 
used as an argument in support of the treatment of gout with piperazine, 
and some clinicians have had very favorable results from it, while others 
have been disappointed. It is said to relieve the discomfort due to the pas- 
sage of gravel in some cases, while failing in others, but it has not been 
shown to be of any value in the treatment of calculus, and the urine of 
patients treated with piperazine has no more solvent action on uric acid than 
normal urine. Piperazine seems to induce no symptoms in man or animals 
even when administered in large quantities. 

Urotropine has been recommended as a solvent for uric acid, and also as a 
genito -urinary disinfectant. It is excreted in the urine and is there partially 
decomposed into formaldehyde, which exercises an antiseptic action in the 
bladder and urethra and may possibly form a soluble combination with uric 
acid. It has no effect on uric acid deposits in birds, any solvent action it 
may exert being confined to the uric acid in the urine. Both piperazine and 
urotropine often cause some diuresis, and this may partly explain the relief 
afforded in gravel. 



554 INORGANIC SALTS, ACIDS AND BASKS. 

Quinic acid has been suggested as a treatment for gout on the theory that 
it would combine with glycocoll in the body and thus prevent the formation 
of uric acid, a theory based on most unsatisfactory grounds. As a matter 
of fact it has no effect whatever on the amount of uric acid excreted. In 
short there is every reason to believe that these new remedies will prove no 
more reliable than the older treatment of gout and the " uric acid diathesis." 

Piperazine is given in solution in doses of 1 G. (15 grs.), urotropine in doses 
of 0.5 G. (8 grs.). 

Bibliography. 

Biesenthal. Berl. klin. Woch., 1892, pp. 28 and 754; 1893, p. 805. 

Mendelsohn. Ibid., 1892, p. 384; 1898, p. 48. 

Meisels. Ungar. Arch. f. Med., Bd. i., p. 364. 

Nicolaier. Ztschr. f. klin. Med., xxxviii., p. 350. 

Richardson. Journ. of Exp. Med., iv., p. 19. 

Ortowski. Ztschr. f. klin. Med., xl., p. 331. 

Lewandowski. Ibid., xl., p. 202. 

Ulrici. Arch. f. exp. Path. u. Pharm., xlvi., p. 321. 

XV. THE ACETATE SERIES. 

As far as their immediate effects are concerned, the acetates of the fixed 
alkalies resemble the chlorides, owing any effect they possess to the salt- 
action. In the tissues however the acetates are oxidized and form car- 
bonates, so that the effects are those of the chloride before absorption, and 
those of the carbonate subsequently. They are probably partly decomposed 
by the hydrochloric acid in the stomach, and in the intestine they are rapidly 
absorbed. The oxidation seems to proceed rapidly, and is very complete, 
over 95 per cent, of the acetate disappearing, and only some 2-3 per cent, 
being excreted unchanged in the urine. The alkalinity of the blood and of 
the urine is increased by the acetates as by the carbonates, and the amount 
of urine is increased. 

The oxidation of the acetates, of course, supplies energy to the body and 
they are therefore foods technically, but they are unable to replace the fats 
and carbohydrates, as they fail to lessen the nitrogenous tissue change (com- 
pare alcohol, p. 142). Practically they are useless as foods, as when given 
in sufficient amount they derange the stomach in the same way as common 
salt and also alter the character and amount of the urine. 

The acetates seem almost devoid of specific action — they act only as salts 
by changing the physical properties of the body fluids or as alkalies after 
absorption. The other members of the acetate series have some action, how- 
ever, for the formate, propionate, butyrate and valerianate of soda have been 
shown to be very weak narcotics when they are injected hypodermically or 
intravenously ; this is especially marked in the case of the butyrate. Rather 
more of the formate escapes unchanged in the urine than of the acetate, 
while the others are apparently entirely oxidized. The butyrate differs from 
the acetate in being capable of taking the place of the carbohydrates and 
fats more completely, and in thus leading to an economy of the nitrogenous 
tissues of the body. 

All of the simpler salts of this series are equally rapidly absorbed from 
the intestine, but the oenanthylate and the caprylate resemble the saline 
cathartics in being very slowly absorbed. Probably this holds also for the 
higher members of the acetic acid series, including the salts formed by the 
decomposition of fats — palmitates, stearates, etc. 

The Lactates resemble the acetates in being almost entirely inactive, but 
they are rather more slowly absorbed than the acetates. They are oxidized 
in the tissues for the most part, and resemble buty rates in limiting the nitro- 
genous waste, at any rate when they are given in moderate quantities. 
Lactic acid is also excreted in the urine, however, in considerable quantity. 



AMMONIA AND CARBONATE OF AMMONIA. 555 

Preparations. 

Potassii Acetas (IT. S. P., B. P.), a crystalline salt of pleasant, saline taste 
and very soluble in water. 1-4 G. (15-60 grs.). 

Sodii Acetas (U. S. P.) resembles the potassium salt. 

Ammonii Acetas. (See page 557.) 

Strontii Lactas (IT. S. P.), 1-2 G. (15-30 grs.). 

Acetate of potash has been largely used as a diuretic and in the treatment 
of gout and rheumatism. It acts here exactly as the alkaline carbonates and 
bicarbonates, but has the advantage of not neutralizing the gastric juice, or 
in any T way affecting the digestion except from its salt-action, which may be 
minimized by exhibiting it in dilute solution. 

The citrates of the alkalies may be used for the same purpose, as they are 
not cathartic except in large quantities. (See Saline Cathartics, p. 540.) 

Bibliography. 

Buchheim. Arch. f. phys. Heilk., 1857, p. 122. 

Mayer. Arch. f. exp. Path. u. Pharm., xxi., p. 119. 

Weiske u. Flechsig. Centralbl. f. Phys., 1890, p. 36. 

Mallevre. Pfluger's Arch., xlix., p. 460. 

Pohl. Arch. f. exp. Path. u. Pharm., xxxi., p. 289 ; xxxvii., p. 413. 

XVI. AMMONIA AND CARBONATE OF AMMONIA. 

Ammonia solution and carbonate of ammonia differ considerably 
from the corresponding hydrates or carbonates of the fixed alkalies in 
their effects. The gas evaporates rapidly from its watery solutions, 
and the carbonate gives off ammonia freely, so that the effects 
are very similar, although the solution of ammonia is much the more 
powerful. Owing to its volatility, ammonia penetrates more rap- 
idly and deeply than the fixed alkalies, and at the same time is less cor- 
rosive and less enduring in its effects. Applied to the skin in concen- 
trated solution, it may corrode to some extent, but ordinary dilute 
preparations act merely as rubefacients, like the volatile oils. Even 
concentrated solutions do not dissolve the epidermis like the fixed 
alkaline hydrates, but tend to penetrate through it and raise blisters. 
When inhaled, the irritation of the nasal mucous membrane causes a 
reflex stimulation of the vaso-motor centre, and consequent contrac- 
tion of the arterioles and augmented blood-pressure, while the respira- 
tion is first arrested, and then becomes deeper and fuller. The heart 
may be temporarily slowed by inhibitory reflexes. Three parts of 
ammonia in 10,000 of air cause sneezing, pain in the nose, and tears, 
when inspired by man, and 5 parts in 10,000 are dangerous when in- 
haled for some time (Lehmann). 

Concentrated solutions cause corrosion of the mouth, oesophagus and 
stomach similar to that seen in poisoning with the fixed alkalies, but 
some of the vapor, passing into the respiratory passages, often sets up 
spasm of the glottis, or such swelling of the mucous membrane of the 
larynx and trachea as to induce asphyxia. In cases of ammonia 
poisoning, therefore, the symptoms often arise, not so much from the 
gastric corrosion as from asphyxia, and death may occur very suddenly 
from this cause. The carbonate of ammonia, when swallowed, also causes 
slight gastric irritation, and in larger quantities nausea and vomiting. 



556 INORGANIC SALTS, ACIDS AND BASES. 

After absorption ammonia and its carbonate are rapidly changed to 
urea, and thus differ from the fixed alkalies in not rendering the blood 
more alkaline, and in having no effect on the urine except to increase 
the urea and thereby cause some diuresis. 

The carbonate of ammonia stimulates the central nervous system 
when it is injected into the blood in some quantity, but it is very 
doubtful whether either the hydrate or the carbonate has any such 
effect when absorbed from the stomach. (Of. Ammonium Chloride, 
page 500.) 

Preparations. 

Aqua Ammonise Fortior (TJ. S. P.), a solution of ammonia in water, con- 
taining 28 per cent, of the gas by weight. 

Liquor Ammonise Fortis (B. P.), 32£ per cent, by weight, 

Aqua Ammonise (U. S. P.), Liquor Ammonise (B. P.), an aqueous solution 
of ammonia of 10 per cent, strength by ^weight. 

Spiritus Ammonise (TJ. S. P.), an alcoholic solution of ammonia containing 
10 per cent, of the gas by weight, 1-2 c.c, (15-30 mins.). 

Spiritus Ammonia Atjomaticus (U. S. P., B. P.), Aromatic Spirit of 
Hartshorn, Spirit of Sal Volatile, contains ammojiia and ammonium carbonate 
along with several volatile oils dissolved in alcohol. 1-4 c.c. (15-60 mins.), 
in a glass of water. 

Linimentum Ammonise (U. S. P., B. P.), ammonia liniment, volatile lini- 
ment, contains about 3.5 per cent, of ammonia (2.5 per cent. B. P.). 

Ammonii Carbonas (U. S. P., B. P.) is not the pure carbonate but a mix- 
ture of somewhat varying composition consisting of carbonate (NH 4 HC0 3 ) 
and carbamate of ammonia (NH 4 NH 2 C0 2 ). It releases ammonia in the air 
and has therefore its pungent taste and smell. It forms translucent, crys- 
talline masses, is very soluble in water and is contained in the aromatic 
spirit of ammonia. 0.2-0.6 G. (3-10 grs.) in dilute solution. 

Ammonia is contained in several of the tinctures of the B. P. (ammoniated 
tinctures) and in the Linimentum Camphorae Ammoniatum, etc. 

Therapeutic Uses. — The aqueous solutions of ammonia are compara- 
tively rarely employed, although the strong solution has been advised 
as a vesicant in cases of renal disease, in which cantharides is contra- 
indicated. The ammonia solution has to be covered by a watch-glass 
in order to prevent its evaporation, and is said to be more painful 
than other vesicants. The liniment is used as a rubefacient in bruises 
and in other similar conditions. The gas arising from ammonium 
carbonate is often inhaled in cases of fainting or collapse, in order to 
elicit reflex stimulation of the medullary centres. The ordinary 
"smelling salts " used for this purpose consist of the carbonate reinforced 
with some of the strong solution and flavored with oil of lavender. 

The aromatic spirits of ammonia and the carbonate (in solution) are 
used as mild gastric stimulants in debility, flatulence and alcoholism, 
and are very efficient for a short time. Large doses of the carbonate 
(2 G.) have been used as emetics, and are less depressant than many 
others, such as tartar emetic or ipecacuanha. 

The carbonate of ammonia and the spirits or even the ordinary 
water of ammonia are often given in cases of collapse or sudden heart 
failure. They are generally administered by the mouth and probably 



OXALATES. 557 

act here not directly on the heart and respiratory centre, as has been 
supposed, but reflexly from gastric irritation. They have also been in- 
jected subcutaneously or even intravenously for this purpose, and here 
the local action may be reinforced by a direct action on the medulla 
oblongata. The action lasts only a very short time, but is often suffi- 
cient to tide the patient over an acute collapse. In depression from 
many different causes the aromatic spirits of ammonia is a favorite 
remedy, and probably owes its value to its gastric action, and not to 
any changes in the central nervous system. The carbonate is often 
added to other expectorant remedies to render the bronchial mucous 
secretion more fluid. (See Ammonium Chloride, page 500.) 

Strong water of ammonia is applied locally in snake-bite, and is 
popularly believed to be very efficacious. It has no effect on the tox- 
aibumins of snake poison, and probably is of little or no value in these 
cases. 

Bibliography. 

See Ammonium Chloride, page 500. 
Lehmann. Arch. f. Hygiene, v., p. 1. 

The Acetate of Ammonia acts in the same way as the chloride 
locally, but undergoes oxidation in the tissues, and the whole is changed 
to urea, so that the ammonia of the urine is not increased, but only the 
urea. In the form of its solution, the spirit of Mindererus, it is used 
as a diaphoretic and diuretic, and is often prescribed along with more 
powerful remedies in fever. 

Preparations. 

Liquor Ammonii Acetatis (IT. S. P., B. P.), spirit of Mindererus, contains 
about 7 per cent, of the acetate with some free acetic acid and carbonic acid 
and must be freshly prepared. 10-25 c.c. (2-6 fl. drs.). 

Liquor Ammonii Citratis (B. P.) resembles the solution of the acetate. 
2-6 fl. drs. 

XVII. OXALATES. 

The oxalates (NaOOC — COONa, sodium oxalate) differ from the acetate 
series is not undergoing oxidation in the tissues, and in being poisonous to 
most forms of living matter. This poisonous action is shown in the frog by- 
depression and final paralysis of the central nervous system, the brain being 
first affected, then the medulla oblongata and spinal cord. Later still, the 
terminations of the peripheral nerves and the muscles and heart are para- 
lyzed, twitching and fibrillary contractions of the voluntary muscles often 
being observed first. 

In mammals there is apparently at first a stimulation of the medullary 
centres, for rapid, deep breathing occurs in the rabbit, and vomiting and 
nausea in the dog, and according to some observers, the arterial tension is 
first increased through stimulation of the vaso-motor centre. Later the 
movements are wanting in coordination, the respiration becomes slow and 
dyspnoeic, the heart is weak, and the animal becomes comatose and dies, 
sometimes in convulsions. 

In cases of oxalate poisoning in man, the early symptoms are great mus- 
cular weakness, twitching of the muscles, especially of those of the face, 



558 INORGANIC SALTS, ACIDS AND BASES. 

more rarely convulsions ; later there follows collapse with a weak, fluttering 
pulse, pallor or cyanosis, coma and death. 

Oxalates are very poisonous to all forms of animal life and to plants con- 
taining chlorophyll, but are harmless to the moulds, bacteria and some algae. 
They are absorbed with great difficulty from the stomach and intestine, and 
cause irritation and effusion of liquid except in very dilute solutions. Added 
to the blood outside or inside the body, they prevent its coagulation, and the 
rennet ferment also fails to coagulate milk in the presence of small quanti- 
ties of oxalate (see Calcium). The frog's heart is very much weakened by 
the addition of oxalate of soda to the blood perfused through it, while the 
mammalian heart is not affected by very small quantities, but if the injection 
of oxalate be continued, becomes suddenly weaker. The action on the cen- 
tral nervous system has been mentioned already, and consists in depression, 
which is sometimes intermixed with, or preceded by symptoms of stimulation. 

When the ordinary nerve-muscle preparation is soaked in oxalate solution, 
the same twitching and tremor of the muscle is observed as when the salt is 
injected into the frog. Later the nerve ends are paralyzed, and the nerve 
fibres lose their irritability, as is indicated by the disappearance of the elec- 
trical current of action. The muscle is extremely weak, and according to 
several observers, loses its irritability, while Locke finds that it can be made 
to contract locally by strong currents, even after being soaked for several 
hours. The post-mortem rigor does not seem to be prevented by oxalate as 
has been stated by some observers. 

Oxalate solutions precipitate lime salts, and as it is well known that lime 
is an essential constituent of living matter, it has been suggested that the 
oxalates cause these changes in the organism not through any direct action 
on protoplasm, but through their precipitating the calcium and thus chang- 
ing its ordinary relation to the proteids. This explanation has been sup- 
ported by the discovery that calcium salts added after oxalates restore the 
lost function in many cases, although this of course admits of the explana- 
tion that the calcium merely throws the oxalate out of solution, and does not 
really supply fresh lime to the tissues. The presumption is strong however 
that the action of the oxalates is due, at any rate in part, to their precipi- 
tating the calcium in the tissues, although they may have a specific action 
on living matter in addition. 

The alkalinity of the blood was found to be much reduced by the admin- 
istration of neutral oxalates (Meyer), and it has been surmised that this is 
because the oxidation of the tissues is retarded by the presence of oxalates 
in the blood. This may account for the appearance of a reducing body in 
the urine of animals poisoned with oxalate ; it sometimes occurs in poisoning 
in man and is said not to be dextrose. 

Practically the whole of the oxalate ingested is excreted in the urine in 
the form of oxalate of calcium, and the insoluble crystals are often deposited 
along the urinary tubules and may stop them up entirely and thus cause 
anuria, congestion and inflammation of the kidney ; albuminuria is often the 
most marked symptom in slight poisoning in man. The deposits of oxalates 
often form white lines running from the base to the apex of the renal pyra- 
mids, which are quite evident macroscopically at the autopsy. Small oxa- 
late calculi have also been produced in the pelvis of the kidney, bladder, 
or ureter through the prolonged administration of oxalate or oxamide to 
animals. Not infrequently these renal changes are the only lesions found 
post-mortem in cases of poisoning with oxalates. 

The prolonged administration of oxalates to animals has been found to 
induce changes in the skeleton, for sheep fed on plants containing much ox- 
alate, are found to have less lime in the bones than usual, and in rabbits 
symptoms of rickets are said to be induced from the lessened absorption of 
lime. 

The other members of the oxalate series, malonates (CH 2 (COONa) 2 ) and 
succinates ((CH 2 ) 2 (COONa) 2 ), differ from the oxalates in being very much 



ACIDS. _ 559 

less poisonous, the fatal dose of malonate of soda being about twenty times 
that of the oxalate, and the succinate being almost indifferent. The malo- 
nate is almost completely oxidized in the tissues, and succinate disappears 
completely. It is significant that malonic and succinic acids form much 
more soluble salts with lime than does oxalic acid. Both malonate and suc- 
cinate of soda are absorbed only slowly from the intestine, and act as saline 
cathartics. 

The oxalates are not used in therapeutics. In cases of oxalate poisoning 
the natural antidote is lime, which forms an insoluble precipitate in the 
stomach and may also relieve the symptoms induced by the withdrawal of 
lime from its normal combination in the tissues. At the same time large 
quantities of water and diuretics may be given in order to wash out the 
crystals of oxalate from the urinary tubules. 

Bibliography. 

(See Calcium.) 

.Robert u. Kussner. Virohow's Arch., lxxviii., p. 209. 

Koch. Arch. f. exp. Path. u. Pharm., xiv., p. 153. 

Gaglio. Ibid., xxii., p. 246. 

Pohl. Ibid., xxx vii., p. 413. 

Krohl. Arb. a. d. pharm. Inst, zu Dorpat, vii., p. 130. 

Meyer. Arch. f. exp. Path. u. Pharm., xvii., p. 304. 

Neuberger. Ibid., xxvii., p. 39. 

Ebstein u. Nicolaier. Virchow's Arch., cxlviii., p. 366. 

Ringer. Practitioner, xxxiv., 1885, p. 81. 

Locke. Journ. of Phys., xv., p. 119 ; xvii., p. 293. 

Howell. Ibid., xvi., p. 476. 

Loew. Ein natiirliches System der Giftwirkungen, 1893. 

Heymanns. Arch. f. Anat. u. Phys., 1889, p. 168. 

Marfori. Arch. Ital. de Biol., xxvi., p. 194. 

Nathusius. Centralbl. f. Phys., 1897-98, p. 608. 

Neither g. Inaug. Diss., Dorpat, 1893. 

Vietinghoff-Scheel. Arch, internat. de pharmacodyn. , viii., p. 225. 

XVIII. ACIDS. 

Some acids owe their activity in the organism almost entirely to 
their acidity, i. e., to the hydrogen ion, which is much more powerful 
than the potassium ion, but otherwise stands on the same plane with 
it ; those acids may therefore be treated of together. In the case of 
many other acids such as prussic or salicylic acid, the effects of the 
acidity or hydrogen ion is insignificant in comparison with those of the 
rest of the molecule or the negative ion, and these are treated along 
with their salts. 

Action. — The acids owe their action on living tissues to their neu- 
tralizing alkalies, to their withdrawing water, when in concentrated 
form, and to their precipitating some of the proteids, more especially 
the globulins. 

Most living matter is neutral or slightly alkaline in reaction, and 
seems to be incapable of existing in acid media. Exceptions are met 
with in some of the moulds and in other vegetable organisms which 
live in somewhat acid solutions, but even these are destroyed by more 
concentrated solutions, perhaps because the acids precipitate their pro- 
teids. Acids are therefore Protoplasm Poisons and antiseptics of some 
power. Hydrochloric acid is found to delay the growth of organisms, 



560 INORGANIC SALTS, ACIDS AND BASES. 

and even to destroy the great majority of the less resistant forms in 
0.2-0.3 per cent, solution, or in the percentage in which it exists 
in the gastric juice. The others vary in strength largely according to 
their acidity, that is, according to the number of hydrogen ions, or 
the amount of dissociation. The anion has also some effect in many 
cases. 

When sulphuric or nitric acid is applied to the Skin in concentrated 
form, it acts as a powerful caustic, destroying the epidermis and pene- 
trating to some distance into the skin and subcutaneous tissues, in 
which it causes necrosis. This is of course accompanied by great 
pain, and if much of the skin is attacked, by shock and collapse and 
symptoms similar to those seen in severe burns. Sulphuric acid causes 
a white, later a brown or black eschar, nitric acid a yellow. Hydro- 
chloric acid is less liable to cause wholesale destruction of the skin, 
but penetrates the epidermis and raises blisters. The organic acids 
and phosphoric acid are still less irritant, but cause redness and even 
blistering when applied in concentrated solution. Dilute solutions of 
the acids may act as slight irritants to the skin, and often cause a feel- 
ing of stiffness and numbness, perhaps from precipitating the proteids. 

The corrosive action of the acids is much more marked when they 
are applied to the less resistant Mucous Membranes. Even small quan- 
tities of strong sulphuric acid striking the eye are sufficient to destroy 
the sight. 

In the Mouth, (Esophagus, and Stomach the corrosive action is evi- 
denced by complete destruction of the mucous membranes which come 
in contact with the strong acid. The oesophagus and stomach may be 
perforated, and this, along with the shock and collapse, often proves 
immediately fatal, or if the patient recovers temporarily, the erosions 
may give rise to cicatricial contractions and death from inanition. 
Hydrochloric acid and the stronger organic acids are capable of caus- 
ing corrosion of the mucous membranes, but this is not so extensive 
generally as that following nitric and sulphuric acid. The corrosion 
from acids differs from that from alkalies, in the tissues being shrunken, 
hard and brittle, while after a caustic alkali they are soft and swollen 
and have a slimy soapy appearance. 

The symptoms of corrosive acid poisoning are intense pain in the 
mouth, throat and stomach, vomiting and often diarrhoea, shock and 
collapse, with rapid, weak pulse and shallow respiration. The tem- 
perature is often subnormal, and death occurs in the course of a few 
hours. When fuming acids are swallowed, and especially in poisoning 
with hydrochloric acid, the irritant vapor passing into the respiratory 
passages may cause spasm of the glottis, or oedema of the larynx, and 
prove immediately fatal from asphyxia. Even one part of hydro- 
chloric acid vapor in 20,000 of air causes sneezing and pain in the 
throat and chest (Lehmann). 

Dilute solutions of the acids have a characteristic taste, and induce a 
reflex flow of saliva and an astringent feeling in the mouth and throat 
from their causing a coagulation of the superficial layers of proteids. 



ACIDS. 561 

In the stomach they displace any weaker acids from their combinations 
with bases, and may have some antiseptic action. The gastric juice is 
normally acid, containing about 0.2 per cent, of free hydrochloric acid, 
and this acid reaction is essential to the action of pepsin. Other acids 
may replace the hydrochloric acid in digestion, and a good deal of 
work has been done in determining the relative value of the acids for 
this purpose. This is done by adding different acids to solutions of 
pepsin in test-tubes, and noting the amount of fibrin or other proteid 
which is digested in the course of a number of hours. These experi- 
ments have shown that hydrochloric is better than most other acids, 
but is perhaps surpassed by hydrofluoric and oxalic acids ; but the re- 
sults seem to vary with the particular pepsin used, that obtained from 
the dog and calf differing somewhat in its relations to acids from that 
of the child. Their poisonous action precludes the use of either flu- 
oric or oxalic acid in the stomach, and the other acids seem inferior to 
hydrochloric acid, so that both clinical experience and experiment 
point to the last as the most suitable acid for use in the stomach. 

The acids are absorbed from the alimentary canal fairly rapidly in 
most cases. In the Blood and Tissues they do not exist as acids but 
as salts, for the reaction of the blood must remain slightly alkaline 
throughout life, and if sufficient acid be given to neutralize the alka- 
lies of the body, the animal dies before the blood becomes neutral, al- 
though after death it may be found to be acid. The means provided 
by the economy to neutralize acids differ in different animals ; in the 
herbivora the fixed alkalies of the blood and tissues are called upon 
chiefly, and if more acid be absorbed than can be neutralized by these, 
the animal dies ; in the carnivorous animals and in man, a further pro- 
tective mechanism exists, for in these ammonia is liberated by the tis- 
sues, and serves to neutralize the acid, and thus saves the fixed alka- 
lies. The difference is relative and not absolute, however, for the 
herbivora also develop some ammonia, and the carnivora employ some 
of the fixed alkalies to preserve the normal reaction of the tissues. 
Man appears to stand midway between the two classes, for while am- 
monia appears in the urine after acid absorption, the fixed alkalies are 
also present in excess. Much larger amounts of dilute acids may 
therefore be absorbed without serious symptoms by man and by the 
carnivora than by the herbivora. The explanation of this difference 
between the flesh-eating and the plant-eating animals is to be found in 
the nature of their food. The flesh-eaters are accustomed to the for- 
mation of some acid in their tissues, because the alkalies of their food 
are insufficient to neutralize the acids formed by the oxidation of the 
organic matter, and they would gradually be deprived of all their al- 
kaline salts, therefore, were they not protected by the formation of 
ammonia. On the other hand, the herbivorous animals absorb much 
larger quantities of the organic salts of the alkalies in their food, and 
these forming carbonates in the body, serve to neutralize what acid is 
formed in the tissues. In ordinary circumstances, therefore, they have 
no need to protect the fixed alkalies, and are unprovided with any 
36 



562 INORGANIC SALTS, ACIDS AND BASES. 

mechanism for this purpose. When an excess of acid is absorbed, 
they neutralize it by means of the fixed alkali of the tissues and blood, 
and this leads to a lessened alkalinity of the blood, which becomes 
unable to carry so much carbonic acid from the tissues to the lungs. 
Thus in acid poisoning in rabbits, the alkalinity of the blood has been 
found to be so greatly reduced that instead of containing some 25 vol- 
umes of carbonic acid per cent, of blood, it carried only two volumes 
per cent, or very little more than could be dissolved in the same 
amount of water. When this occurs, the tissues are unable to rid 
themselves of their carbonic acid, 1 and a series of symptoms follow, 
commencing in deep, labored, rapid, afterwards shallow respiration ; 
the heart is weak, a condition of collapse follows, and eventually the 
respiration ceases, the heart continuing to beat for some time longer. 
The quantity required to poison a rabbit in this way is about 1 G. of 
hydrochloric acid for each kilogm. body weight. The injection of 
sodium carbonate, even in the last stage of intoxication, is followed by 
rapid recovery, from more alkali being supplied the blood and tissues, 
while other carbonates are not so useful owing to the action of the 
basic ion. The blood-pressure in rabbits is much reduced by the acids, 
from depression of the vaso-motor centre and the heart. In carnivora 
and man, the absorption of dilute acids does not alter the alkalinity of 
the blood to any marked degree, and no serious symptoms arise from 
this cause. 

The salts formed in the blood and tissues after the absorption of 
acids are rapidly Excreted by the kidneys, which however retain as 
much alkali as possible in the body and thus excrete the salts in an 
acid form, and perhaps some free acid. Hence there arises in some 
cases irritation of the kidneys, with albumin and even blood in the 
urine, which is rendered more acid than usual and causes a sensation 
of heat and smarting in the bladder and urethra. In the herbivora, 
the reaction changes from alkaline to strongly acid, and large quanti- 
ties of the salts of the alkalies appear, while in the carnivora some 
increase in the sodium and potassium of the urine occurs along with 
a much greater increase in the ammonia. The total nitrogen is some- 
what increased from the large amount of ammonia, but the urea is 
slightly decreased. Some authors have found an augmented excretion 
of lime in the urine, while others state that it is less than usual. 

Not infrequently fatty degeneration of the heart, liver, muscles or kidney 
has been observed in corrosive acid poisoning, when the patient survived 
for a few days, and Fraenkel and Reich e found a form of necrosis of the renal 
cells in these cases. These changes are not due to free acid in the blood, 
but their exact cause has not been satisfactorily determined. 

The prolonged treatment of animals with acids has been found to be fol- 
lowed by anaemia and loss of flesh and strength, which are probably attri- 
butable to the disturbance of the digestion and not to any specific action of 
the acids. 

1 This is the explanation universally adopted, but Loewy and Munzer have recently 
shown that some additional factor is involved in the action of acids on herbivora. 
Spiro states that in some cases the acid is excreted in the urine with greater difficulty 
in the herbivora than in the carnivora- 



ACIDS. 563 

Acids applied directly to the living tissues lessen their vitality, and un- 
less there is sufficient alkali present to neutralize them, soon destroy it 
entirely. In some cases they tend to cause a temporary increase in activity 
at first ; thus the cilia of ciliated epithelium have been found to move more 
rapidly at first in very dilute acids and then to cease all movement, while 
muscle seems to be rendered weaker and less irritable at once. As in the case 
of alkalies, Loeb finds that dilute acid causes muscle to imbibe more water 
than salt solution does, and Hamburger finds that the red blood cells are 
increased in size by the addition of small quantities of acid to the blood out- 
side the body. The frog's heart is weakened and dilated by the addition of 
acid to a perfusing solution, and the muscular wall of the vessels also re- 
laxes. The addition of acids to the blood tends to destroy the red cells and 
to decompose the haemoglobin. 

Therapeutic Uses. — The acids are used in medicine only to a limited 
extent, and some of the official preparations might well be dispensed 
with. 

They may be employed to give flavor to draughts in fever and in the thirst 
of diabetes, the most popular forms being those formed from fruits, such as 
lemons, limes, or grapes. The taste is due to the sugars, acids, and volatile 
oils of the fruits, and is modified by the presence of inert colloid substances, 
such as the pectins. The acids, of which citric, tartaric and malic are the 
chief, are very important factors in the effect, for if these be neutralized, the 
fruit juices become insipid, and do not quench thirst so thoroughly. The so- 
called grape cure, in which very large quantities of grapes are eaten, owes 
most of its value to the large amount of water taken, although the acids and 
salts may act as aperients in the same way as the saline cathartics. Instead 
of the fruit juices, carbonic acid waters may be advised, and occasionally 
other acids, such as phosphoric or sulphuric, are prescribed to give flavor. 

Acids are also used in certain forms of dyspepsia in which the hy- 
drochloric acid of the stomach is deficient. Hydrochloric acid is most 
frequently prescribed for this purpose, although nitric and nitrohydro- 
chloric acids have also some reputation ; the hydrochloric acid is 
certainly more efficient than these in test-tube experiments on di- 
gestion. The forms of dyspepsia thus treated are generally those aris- 
ing from a sedentary life or in the course of convalescence, and the 
acids are often prescribed along with the bitter stomachics and are to 
be taken about half an hour before meals. Irritation of the stomach, 
or hyperacidity of the gastric juice is of course a contraindication. It 
is to be remarked that recent researches on the gastric juice have shown 
that the pepsin is excreted in actual combination with the hydro- 
chloric acid, so that it would seem to be impossible to completely re- 
place the deficiency of acid in the stomach by giving hydrochloric acid 
by the mouth. 

In cases of alkaline poisoning, the acids are the natural treatment ; 
the organic acids should be preferred for this purpose, as they are less 
liable to cause additional corrosion, and acetic acid in the form of vine- 
gar is more likely to be at hand than any other. 

In every case in which acids are prescribed internally, they have to 
be given largely diluted, as otherwise they irritate the throat and 
stomach. They are taken through a glass tube, in order to prevent 
as far as possible their action on the teeth. 



564 INORGANIC SALTS, ACID AND BASES. 

Strong acids have some effect in arresting haemorrhage (styptics) 
when applied directly to the bleeding point, but are much inferior to 
some of the metallic salts, such as the iron perchloride. 

Externally, the acids are used to some extent as corrosives, strong 
nitric acid being not infrequently used to destroy small tumor*, to 
cauterize the os uteri and for similar objects. Its action is more easily 
localized than that of potash and on the other hand is more powerful 
than the metallic salts such as silver nitrate and zinc chloride. In 
dilute solution, they are sometimes applied to the skin to lessen ex- 
cessive local sweating and diluted vinegar is often used to sponge fever 
patients. 

In cases of corrosive Poisoning with acids, the first indication is to 
neutralize the acids as far as possible by giving alkalies. These ought 
not to be in themselves corrosive, and the best antidote is therefore 
the insoluble magnesia and magnesium carbonate. Lacking these, 
the most readily accessible alkali is the best, and the lime may be 
scraped from walls or ceiling, or chalk, soap, or wood ashes may be 
given. The walls of the stomach and oesophagus may also be pro- 
tected by giving milk or white of egg, or the acid may be rendered 
less corrosive by diluting it with large quantities of water. 

Bibliography. 

Walter. Arch. f. exp. Path. u. Pharm., vii., p. 148. 
Salkowski. Virchow's Arch., lviii., p. 1. 
Jacquet. Arch. f. exp. Path. u. Pharm., xxx., p. 311. 
Hahn. Virchow's Arch., cxxxvii., p. 597. 
Jaworski. Deutsch med. Woch., 1887, Kos. 36-38. 

Hiibner. Fortschritte der Med. , xii., p. 163. 
Fraenkel u. Rekhe. Virchow's Arch., cxxxi., p. 130. 

Wroblewski. Zeitschr. f. phys. Chem., xxi., p. 1. 
Runge. Arch. f. exp. Path. u. Pharm., x., p. 324. 
Freudberg. Virchow's Arch., cxxv., p. 566. 
Dunlop. Journ. of Phys., xx., p. 82. 
Loeb. Pfliiger's Arch., lxix., p. 1 ; lxxiii., p. 422. 

Winterberg. Ztschr. f. phys. Chem., xxv., p. 202. 
Limbeck. Ztschr. f. klin. Med., xxxiv., p. 419. 
Loewy u. Munzer. Arch. f. [Anat. u.] Phys., 1901, p. 81. 
Spiro. Beitrage z. phys. und path. Chemie, i., p. 269. 
Compare Alkaline Hydrates and Carbonates, page 553. 

For the specific effects of the anions of the acids, see chlorides, phosphates, acetates, 
oxalates, etc. 

Sulphuric Acid. 

Sulphuric acid is one of the most corrosive acids when it is applied in 
concentrated form, and often induces complete charring of the tissues, and a 
coal-black slough. 

Acidum Sulphuricum (IT. S. P., B. P.), concentrated sulphuric acid, con- 
taining at least 92.5 per cent, by weight of absolute sulphuric acid U. S. P., 
containing 98 per cent. B. P. 

Acidum Sulphuricum Dilutum (U. S. P., B. P.) contains 10 per cent. IT. S. P., 
13.65 per cent. B. P. of absolute sulphuric acid. 0.6-2 c.c. (10-30 mins.). 

Acidum Sulphuricum Aromaticum (U. S. P., B. P.) is an alcoholic solution 
flavored with ginger and cinnamon. The U. S. P. preparation contains 20 
per cent., the B. P. preparation 13.8 per cent, of sulphuric acid. 0.3-1 c.c. 
(5-15 mins.) in a glass of water. 



ACIDS. 565 

Sulphuric acid and its preparations are not largely used. It is occasionally 
applied as a caustic, but nitric acid is generally preferred. Internally it is 
largely used as a prophylactic and remedy in lead poisoning, but it is prob- 
ably of little value here. (See Lead.) It has also been advised in a number 
of conditions, such as diarrhoea, cholera, night sweats, but has not proved 
efficacious in any of them. When prescribed internally the aromatic acid is 
the best form, but sulphuric acid could be dispensed with entirely in thera- 
peutics. 

Nitric Acid. 

Mtric acid is equally or even more corrosive than sulphuric acid. It 
stains the skin and tissues a bright yellow or yellowish-brown, and this 
serves to distinguish cases of poisoning under the two acids. 

Acidum Nitricum (U. S. P., B. P.) contains 68 per cent, of absolute nitric 
acid (HN0 3 ) (B. P. 70 per cent.). 

Acidum Nitricum Dilutum (U. S. P., B. P.) contains 10 per cent. U. S. P., 
17.44 per cent. B. P. by weight of absolute nitric acid. 0.6-2 c.c. (10-30 
mins.). 

A glass rod dipped in concentrated nitric acid is used as a corrosive. The 
dilute acid has been advised in dyspepsia, but is generally considered in- 
ferior to hydrochloric acid, and has been shown to be much less efficient in 
artificial digestion. It has also some reputation in certain liver diseases, 
but is supposed to be inferior to the nitrohydrochloric acid. Nitric acid is 
occasionally used in some intestinal conditions accompanied by diarrhoea. 

Hydrochloric Acid. 

Hydrochloric acid is less corrosive than the two preceding acids, and 
tends to cause blistering on the skin rather than necrosis. It may cause 
actual loss of substance, however, when applied to the mucous membranes 
in concentrated form, and stains the mouth a whitish color. 

Acidum Hydrochloricum (U. S. P., B. P.), muriatic or hydrochloric acid, 
contains 31.9 per cent, by w T eight of the gas HC1. (B. P. 31.79 per cent.) 

Acidum Hydrochloricum Dilutum (U. S. P., B. P.) contains 10 per cent. 
(B. P. 10.58 per cent.) of hydrochloric acid gas. 0.3-2 c.c. (5-30 mins.) in 
a glass of water. 

Concentrated hydrochloric acid is scarcely used in therapeutics. The 
diluted acid is often prescribed in dyspepsia in which there seems to be a 
deficiency of the natural acid secretion. In cases of diarrhoea in which 
excessive putrefaction of the intestinal contents is present, it may be of 
benefit when prescribed along with other drugs ; this action is probably 
explained by its disinfecting the stomach contents, as the hydrochloric acid 
of the gastric secretion normally does ; for the double sulphates of the urine 
certainly diminish under its use in many cases. It is said that hydrochloric 
acid prevents the lactic fermentation in 1 : 1,000 dilution, and that in addi- 
tion to its action on the digestive ferment it increases the peristalsis of the 
stomach. 

Bibliography. 

Cohn. Zts. f. phys. Chem., xiv., p. 74. 
Hirschfeld. Pfl tiger's Arch., xlvii., p. 510. 
Kast. Maly's Jahresbericht, 1889, xix., p. 271. 
Schuele. Ztschr. f. klin. Med., xxix., p. 67. 
Lehmann. Arch. f. Hygiene, v., p. 1. 

Nitrohydrochloric Acid. 

Nitrohydrochloric acid is formed by mixing hydrochloric and nitric acid, 
and contains not only the original acids, but a number of decomposition 
products, such as chlorine, nitroxychloride (NOC1) and nitrous acid. The 



566 INORGANIC SALTS, ACIDS AND BASES. 

strong acid (aqua regia) is the most powerful solvent and oxidizing agent 
known, dissolving such refractory metals as platinum and gold. 

Acidum Nitrohydrochloricum (U. 8. P.), nitromuriatic acid, aqua regia, is 
formed by mixing 180 parts of nitric acid with 820 parts of hydrochloric acid. 

Acidum Nitrohydrochloricum Dilutum (U. S. P.) is formed by mixing 40c.c. 
of nitric acid with 180 of hydrochloric and diluting the whole to one litre. 
0.5-1 c.c. (5-15 mins.). 

Acidum Nitrohydrochloricum Dilutum (B. P.) is formed by mixing 6 parts 
of nitric acid and 8 parts of hydrochloric acid with 50 of distilled water. 
5-20 mins. 

The diluted acid alone is used in therapeutics, and does not seem so efficient 
in ordinary dyspepsia as the dilute hydrochloric acid, but has some reputation 
in the treatment of liver diseases and jaundice, though no explanation of its 
action in these conditions has been offered. The acids cannot act as such 
except in the alimentary canal, but in the nitrohydrochloric acid other con- 
stituents, such as chlorine, are present, and it is conceivable that some of 
these may have a specific effect on the liver ; further proof would seem to 
be required, however, that the treatment is really of value. The acid is 
ordinarily given by the mouth, but some authorities advise that it be applied 
in the form of a foot-bath or of an ordinary bath, and others apply it in a 
compress over the liver. These external applications are stated to be even 
more efficacious in hepatitis than the internal administration, and this serves 
only to strengthen the doubt of the value of the remedy, for it is contrary 
to all experience that such bodies should be absorbed in any quantity from 
the skin, and their local action as cutaneous irritants does not differ from 
that of other drugs. 

Phosphoric Acid. 

Phosphoric acid is much less corrosive and irritant than the other mineral 
acids, but in large, concentrated doses may cause gastro-enteritis. 

Acidum Phosphoricum (U. S. P.) contains 85 per cent., Acidum Phosphori- 
cum Concentratum (B. P.), 66.3 per cent, of absolute phosphoric acid (H 3 P0 4 ). 

Acidum Phosphoricum Dilutum (U. S. P., B. P.) contains 10 per cent., U. S. 
P., and 13.8 per cent., B. P., of phosphoric acid. 0.3-1.3 c.c. (5-20 mins.). 

Phosphoric acid has been used to some extent to form cooling draughts in 
fever. It has also been prescribed in various cachectic conditions on the 
thecry that these were due to a deficiency of phosphates in the food and 
tissues ; but it has never been shown to be of any benefit, and experiments 
have proved that the animal tissues are unable to build up phosphorus 
compounds from the inorganic phosphates. 

Sulphurous Acid. 

Sulphurous acid differs from the preceding members of the group in 
its powerful reducing action, through which it becomes oxidized to sul- 
phuric acid, and which renders it strongly poisonous to protoplasm in 
general, quite apart from its acidity. Sulphurous acid anhydride is 
accordingly used to a considerable extent to disinfect rooms and furni- 
ture after infectious diseases ; for this purpose sulphur is burned in the 
room, which ought to be rendered as air-tight as possible, and the 
fumes are allowed to act for several hours before the room is ventilated. 
The value of this method of disinfection has been called in question, 
but there is no doubt that sulphurous acid gas is fairly germicidal when 
it is applied along with moisture. It is not capable of such a wide ap- 
plication as formaline, because sulphurous acid bleaches many coloring 
matters, and the procedure is open to the objection that it may lend a 



ACIDS. 567 

sense of security which is quite unwarranted, and may lead to the neg- 
lect of other measures. The disinfection to be of any value must be 
thoroughly carried out, and can ouly be applied to inanimate objects, as 
the fumes are fatal to the higher animals, even when much less concen- 
trated than are necessary to destroy bacteria. In order to be of service, 
at least one volume of S0 2 ought to be present in each hundred volumes 
of air, and even this concentration is insufficient to destroy the spores of 
bacteria. Xovy l recommends 3-6 pounds of sulphur to be burned for 
each 1,000 cubic feet of space; the walls and floor should be sprayed with 
water, and the room must be kept perfectly closed for at least 20 hours. 

The chief symptoms of poisoning with sulphurous acid are those of 
irritation of the mucous membranes, and if the solution be swallowed 
these may not differ from those of the other acids. Sulphurous acid 
penetrates the tissues more rapidly than most of the others owing to 
its gaseous form, and does not cause actual loss of substance as sul- 
phuric acid does. 

In poisoning from the inhalation of the anhydride on the other hand, 
the symptoms arise chiefly from the respiratory tract. Even in five parts 
in 10,000 it acts as an irritant, causing sneezing, coughing and lachry- 
mation, and in somewhat greater concentration it becomes entirely ir- 
respirable ; still smaller quantities in the air cause bronchial irritation 
and catarrh, when inhaled for some time. Sulphurous acid is neu- 
tralized and oxidized for the most part to sulphates in the tissues, or 
probably partly in the course of absorption. 

The solution of sulphurous acid of the pharmacopoeia is used to a 
limited extent as an antiseptic solution in skin diseases. It is more 
irritant to the broken skin than many other equally powerful antiseptics. 

Acidum Sulphurosum, U. S. P. — A solution of not less than 6.4 per cent, 
by weight of sulphurous acid gas (S0 2 ) in water. B. P., a solution contain- 
ing 6.4 per cent, of hydrogen sulphite (H 2 S0 3 ) corresponding to 5 per 
cent, by weight of sulphurous anhydride (S0 2 ). 

Hydrofluoric Acid is strongly corrosive and prevents the growth of bac- 
teria in solutions of one per mille. After absorption it induces the specific 
fluoride action (see page 525). 

Organic Acids of the Fatty Series. 

The organic acids have a much less marked local action than the inor- 
ganic, causing little or no corrosion unless when applied to mucous surfaces 
in very concentrated form. They are absorbed as salts of the alkalies, but 
do not as a general rule reduce the alkalinity of the blood or render the 
urine more acid, because they are oxidized to carbonates in the tissues. Ox- 
alic acid is the chief exception to this rule, but the specific action of the ox- 
alates is powerful enough to conceal the acid action to a great extent. 

Acetic Acid applied in concentrated solution to the skin causes irritation 
and congestion and eventually blistering, but does not induce necrosis ex- 
cept of the most superficial layers. The congestion is often followed by 
marked pallor instead of by blistering ; and this has been explained by con- 
traction of the vessels, but may be due to a precipitation of the proteids of 
the skin. In the mouth and stomach it acts as an irritant, causing vomiting, 
great pain, collapse and even death ; the epithelium is found thickened 

1 Novy and Waite. Medical News, lxxii., p. 641. 



568 INORGANIC SALTS, ACIDS AND BASES. 

and occasionally contains haemorrhages. Dilute acetic acid (vinegar) has 
little effect apart from its acid taste, and is used largely as a flavoring agent 
and condiment. The prolonged use of large quantities may however give 
rise to gastric irritation and to loss of appetite and weight. 

Acidum Aceticum Glaciate (U. S. P., B. P.) (HC 2 H 3 2 ) is almost absolute 
acetic acid (99 per cent.), and becomes crystalline at a temperature some- 
what below 15° C. (60° F.). 

Acidum Aceticum (U. S. P., B. P.) contains 36 per cent, of absolute acetic 
acid U. S. P., 33 per cent. B. P. 

Acidum Aceticum Dilutum contains 6 per cent, of absolute acetic acid 
U. S. P., 4.27 per cent. B. P. Dilute acetic acid is used to form the official 
aceta except the Acetum Cantharidis, B. P., 2-8 c.c. Q— 2 fl. drs.). 

Acetic acid is sometimes applied to the skin as a slight local irritant in 
contusions, and in very dilute solutions to cool the surface and to prevent 
excessive local perspiration. It has been used as a styptic in slight haemor- 
rhage, and may be inhaled for this purpose in epistaxis. Vinegar is also 
inhaled in cases of fainting, in order to induce a reflex stimulation of the 
vaso-motor centre through irritation of the nostrils. In cases of poisoning 
with alkalies vinegar is often the most convenient acid and in addition is 
less likely to do harm than the inorganic acids. 

Acetic acid itself is not used as a corrosive, but one of its derivatives, tri- 
chloracetic acid (CCl 3 COOH), has been employed with good results. 

Formic Acid resembles acetic acid in most points, except that it is more 
volatile and more irritant, that less of it is oxidized in the tissues, and that 
given in large quantities it is said to induce nephritis. It is not used in 
therapeutics. 

The other acids of the acetic acid series resemble acetic acid in their ef- 
fects, but seem to become less irritant as they become more complex and less 
easily dissociated. 

Lactic Acid resembles acetic acid in its behavior in the organism (see 
page 554). It was suggested at one time that sleep following muscular ex- 
ertion was due to the lactic acid formed in the muscles, and this acid was 
therefore recommended as a hypnotic, but has been shown to be of no value 
for this purpose. Rickets, rheumatism and other diseases were also at one 
time attributed to the excessive formation of lactic acid in the tissues, but 
this theory is only of historical interest. Under the impression that lactic 
acid was the normal acid of the gastric digestion, it was at one time used in 
dyspepsia. 

Acidum Lacticum (TJ. S. P., B. P.) is obtained by the fermentation of milk 
sugar or grape sugar, and contains 75 per cent, of absolute lactic acid 
(HC 3 H 5 3 ). It is a colorless liquid of strong acid taste. 

Lactic acid has been used recently as a caustic application to malignant 
ulcers and diphtheritic membranes. 

Oxalic Acid is frequently used as a poison by suicides, either as such or as 
the acid potassium salt (salt of sorrel or essential salt of lemons). Poisoning 
has repeatedly occurred from oxalic acid having been mistaken for magnesium 
sulphate, which it resembles in appearance. The symptoms are those of acid 
poisoning, along with the specific effects of the oxalates (see page 557). 
Oxalic acid is not used in therapeutics, although it has been said to be bene- 
ficial in amenorrhoea. 

Tartaric Acid induces symptoms of gastric irritation when taken in large 
doses, and has been the cause of fatal poisoning in a few cases. It is slowly 
absorbed, and some of it escapes combustion in the tissues and is excreted in 
the urine in the form of the acid tartrate. (See Tartrates, page 539.) 

Acidum Tartaricum (U. S. P., B. P.) (H 2 C 4 H 4 6 ), colorless crystals very 
soluble in water. 0.3-1.3 G. (5-20 grs.). 

Tartaric acid is prescribed with the carbonates and bicarbonates to form 
effervescent draughts ; the tartaric acid ought to be slightly in excess in or- 
der to lend its pleasant acid taste, the usual proportion being about eight 



CALCIUM. 569 

parts of acid to seven parts of sodium bicarbonate. These effervescent mix- 
tures formed with the tartrates act as saline cathartics in large doses (see 
page 541). Tartaric acid may be prescribed in dilute solution with sugar 
and a drop of volatile oil as a lemonade, which is cheaper than that formed 
with citric acid. 

Citric Acid resembles tartaric acid in its action, but appears less irritant, 
and no case of serious poisoning is recorded from its use. It is slowly ab- 
sorbed like tartaric, but seems to be almost entirely oxidized in the tissues. 

Acidum Citricum (U. S. P., B. P.) (H 3 C 6 H 5 0. + H 2 0) resembles tartaric acid 
in its properties for the most part. 0.3-1.3 G. (5-20 grs.). 

Syrupus Acidi Citricl (U. S. P.) is ordinary syrup to which one per cent, of 
citric acid and spirit of lemon have been added, and is used only as a flavor. 

Citric acid is used to form lemonades and effervescent draughts. For 
lemonade 2-4 parts of citric acid may be dissolved in 1,000 parts of water, 
some sugar and a few drops of volatile oil being added. For effervescent 
solutions about 8 parts of the acid may be prescribed along with 7 parts of 
bicarbonate of soda, with directions to dissolve the two powders separately, 
mix the solutions and drink while effervescing. In large quantities this mix- 
ture acts as a saline cathartic ; in smaller quantities it may be used to in- 
crease the alkalinity of the blood, and to render the urine less acid. (See 
pages 541 and 555.) 

Lime juice and lemon juice, which contain considerable amounts of free 
citric acid, are generally preferred to the pure acid for lemonades to quench 
the thirst. Lime juice has been found of great benefit as a prophylactic in 
the treatment of scurvy, but this is not due to the citric acid, but to some 
unknown property of the fruit juices. Citric acid has been used in rheumatic 
affections, without any marked improvement being elicited, according to the 
best observers. 

XIX. CALCIUM. 

The salts of lime are present in very large amount in the tissues of 
animals, and considerable interest attaches to their absorption, excretion 
and general action. They form the great mass of the inorganic con- 
stituents of the bones and teeth of the vertebrates and of the shells of 
the invertebrates. In addition it has been shown of recent years that 
they are present to a considerable amount in the soft tissues and are, 
in fact, essential to many forms of living matter, and to the activity 
of certain ferments. 

Calcium and the other alkaline earths differ from the alkalies in 
possessing comparatively few very soluble salts, and they seldom effect 
such changes in the physical properties of the fluids of the body as 
have been described under salt-action and chloride of sodium. Even 
the soluble salts penetrate with greater difficulty into the various tissues 
of the body, which seem to have much less affinity for them than for 
the salts of the alkalies. The general effect of the calcium ion will first 
be described, and the individual salts will then be taken up in turn. 

Action. — The soluble lime salts are Absorbed with great difficulty 
from the stomach and intestine, and retard considerably the absorption 
of fluid. They would presumably have a cathartic action were they 
not thrown out of solution very readily by the alkaline fluids. In 
addition calcium forms insoluble salts with all of the cathartic acid 
ions, so that no such double effect can be obtained as is seen from mag- 
nesium sulphate. (See Saline Cathartics, page 535.) The great pro- 



570 INORGANIC SALTS, ACIDS AND BASES. 

portion of the lime taken either in the food or as a remedy, unquestion- 
ably leaves the body in the stools entirely unabsorbed, while a small 
quantity of it is taken up from the alimentary canal whether the lime be 
administered in a soluble or in an insoluble form. This small quan- 
tity circulates in the blood, probably in combination with proteids, and 
is slowly excreted, unless there is a deficiency in the supply of lime, 
when it may be utilized by the tissues. When larger quantities are 
thrown into the blood by intravenous or hypodermic injection, the 
calcium of the blood remains abnormally high for some time, but all 
the calcium thus injected is not in the circulation throughout its stay 
in the body. Some of it is temporarily deposited in some unknown 
organ, and is gradually withdrawn and excreted after the first excess 
is eliminated. 

The lime is Excreted in part in the urine, but for the most part 
through the epithelium of the large intestine. Abel and Muirhead 
have shown that some of the calcium ingested in the form of the hy- 
drate is excreted in the urine as calcium carbamate (Ca(C0 2 NH 2 ) 2 ) and 
probably other salts may be eliminated in part at any rate in this 
form. The carbamate is a very unstable salt, and breaks up in the 
urine, freeing carbonic acid and ammonia, while the calcium forms the 
carbonate of lime ; the urine is often alkaline therefore, and smells 
strongly of ammonia. Calcium lessens the phosphates of the urine, 
which may be explained by its forming insoluble phosphates in the 
bowel, and thus preventing the absorption of the phosphates of the 
food. The small quantity of calcium absorbed from the alimentary 
canal has not been shown to have any action except in replacing the 
calcium compounds of the tissues. Except under special circum- 
stances, the calcium of the food is always sufficient to supply the needs 
of the organism, so that lime salts given as remedies have after absorp- 
tion no specific action due to the calcium, but owe their activity to the 
anion exclusively. Thus, calcium bromide may have some effect if 
absorbed, but this effect is due to the bromide ion, and would be the 
same if an equal proportion of sodium bromide were taken up by the 
blood. In the same way calcium hydrate when absorbed owes its ac- 
tivity to its alkalinity (hydro xyl ion) and not to the calcium, and 
apart from the method of its excretion, has the same effect in the tissues 
as an equivalent amount of sodium hydrate. 

Soluble calcium salts injected directly into the blood vessels seem to be 
poisonous, though further study of their action is required. They first 
accelerate and strengthen the heart, and in large quantities bring it to a stand- 
still, and also have a marked effect in contracting the vessels when perfused 
through them. They depress the central nervous system, causing narcosis and 
sleep, during which some authors state that the reflexes remain unaffected, 
while others found them much depressed. These effects are absent when 
the salts are taken up from the bowel, mainly no doubt owing to their slow 
absorption, partly perhaps to their forming albuminous compounds in their 
passage into the tissues. 

Lime Starvation. — Excess of calcium in the organism is therefore 
little to be apprehended from the ordinary methods of administration, 



CALCIUM. 571 

and lime salts are not used in therapeutics to induce changes in the 
organism through their presence in excess in the blood, like other 
remedies such as morphine or strychnine. Another question arises, 
however, namely whether the organism may not be rendered abnormal 
by a deficiency in the supply of lime, and whether this deficiency may 
be remedied by the administration of calcium salts. 

The effects of a deficiency of lime in the food have been the subject 
of several very careful investigations, and while the adult animal does 
not seem to suffer greatly from a very considerable reduction of the 
calcium of the food, young growing animals have at the hands of some 
investigators developed marked abnormalities, resembling closely those 
observed in rickets and osteomalacia in the human subject. In lime 
starvation, as in rickets, there is a lessened deposit of lime in the 
bones, which retain their cartilaginous consistency and show other 
deviations from the normal condition ; in rickets the bones alone are 
involved, while in animals deprived of calcium the soft tissues also 
show a lessened content of lime salts. Deficiency of the lime in the 
food naturally affects young animals more than adults, because the 
former require much more calcium to build up the growing skeleton. 

The effects of the withdrawal of lime have been studied in some Iso- 
lated Organs. Thus Ringer compared the behavior of the frog's heart 
when perfused with solutions of the salts of the alkalies with that of 
one perfused with the same solutions to which minute traces of lime 
were added, and found that the efficiency of the heart was much in- 
creased and that it survived very much longer under the latter condi- 
tions ; Locke has recently shown that a similar relation exists between 
the mammalian heart and the inorganic elements of serum. Lime salts 
exercise a similar effect in voluntary muscle, which survives much 
longer when perfused with salt solution containing calcium than when 
sodium chloride solutions alone are used. Both the heart and skeletal 
muscle eventually cease to contract on electrical stimulation when per- 
fused with physiological salt solution, but recover again when traces of 
lime salts are added to it. In the same way, the irritability of the 
frog's nerve persists much longer in salt solution containing a lime salt 
than in unmixed salt solution, and may be restored by the addition of 
lime, when it has disappeared after the prolonged action of the 0.6 
per cent, chloride of sodium solution. Ciliated epithelium continues 
to wave rhythmically much longer in lime solution than in distilled 
water, in which it swells up and rapidly loses its activity. This prob- 
ably explains the observation that some fish die very soon in distilled 
water but survive in water in which traces of lime are present. Lime 
is also necessary for the development of various ova ; for instance, frog 
spawn kept in water devoid of lime salts fails to develop, or develops 
abnormally. 

Lime salts are also indispensable in some processes which are not 
dependent on the presence of living cells. Thus rennet does not coagu- 
late milk except when a lime salt is present, and the Coagulation of the 
Blood may be prevented by precipitating its calcium salts in the form 



572 INORGANIC SALTS, ACIDS AND BASES. 

of oxalates. Hammersten has recently shown that the lime salts are 
not necessary to the formation of fibrin, for this occurs in oxalate 
solutions if fibrin-ferment be added to fibrinogen. But the fibrin- 
ferment is not formed except in the presence of calcium salts, and when 
oxalates are added to the blood before this ferment is developed, they 
prevent its formation and hinder clotting. When lime salts are added, 
the ferment is liberated and coagulation occurs at once. In other 
words, lime is not necessary for the activity of the fibrin-ferment, but 
for its development from the prothrombin or zymogen, in which it ex- 
ists in the circulating blood. 

Other ferments act in the absence of available lime salts. Thus 
pepsin digests when instead of hydrochloric, oxalic acid is added to it, 
but it is unknown whether pepsin is formed from pepsinogen in the 
absence of lime. 

The higher organisms, both animals and plants, have thus been 
shown to require lime for some of their functions, and it is probably 
necessary for many others in which its importance has not yet been 
recognized. The lowest forms of life, however, including the bacteria 
and some of the moulds, seem to be able to live without it. In order 
to induce the effects of lime starvation, it is not always necessary to 
withdraw lime from the food, for they may be caused by the presence 
of any substance which renders calcium entirely insoluble. Thus, 
oxalate solutions added to the blood or milk, or to the nutrient fluid 
for perfusion of the heart, have the same effects as the withdrawal of 
lime. Food containing large quantities of oxalate salts has in some 
cases induced symptoms in animals resembling those of lime starvation, 
and it seems possible that some of the symptoms of fluoride action are 
also explicable from their precipitating the lime salts of the food and 
of the blood. 

In several instances a curious relationship has been shown to exist be- 
tween the calcium and potassium salts. Thus when a frog's heart is per- 
fused with sodium chloride solution containing a trace of calcium, the move- 
ments are not entirely normal, the contraction being somewhat prolonged 
and the relaxation much retarded. If a trace of potassium chloride is added, 
however, the contraction becomes normal in character. On the other hand 
the effect of potassium on the frog's heart is antagonized by the addition of 
lime. The same holds true for voluntary muscle, the salts of calcium tend- 
ing to neutralize the effects of potassium, and vice versa, and in several other 
relations an antagonism has been observed between these two metals. (See 
Ringer.) 

Another question that has excited much interest recently is the relation 
between sodium and calcium. It has already^ been noted that the frog's 
heart perfused with sodium chloride solution soon ceases to beat, but can be 
restored by the addition of calcium and potassium to the circulating medium. 
The ordinary explanation (Ringer, Howell) is that the calcium and potassium 
are necessary to the activity of the heart and that when pure salt solution is 
perfused, these elements diffuse into it and are lost from the heart muscle ; 
this diffusion is prevented if calcium and potassium be contained in the 
solution, and the heart, retaining the salts essential to its activity, continues 
to beat. Another explanation has been offered by Loeb, who supposes that 
the lime and potassium are not directly essential, but that they neutralize 



CALCIUM. 573 

the poisonous effects of sodium. This poisonous action of sodium has not 
been generally recognized, but is well shown by the behavior of a small fish 
(fundulus) living in salt water, which can be transferred to distilled water 
without injury, thus showing that neither sodium nor calcium is necessary in 
its environment. But if it be put in sodium chloride solution of the same 
strength as sea water it dies, so that sodium is poisonous to it unless when 
antagonized by the other constituents of sea water ; the essential elements 
are calcium and potassium, for when these are added to the injurious sodium 
solution, the fish lives as well as in sea water. This series of experi- 
ments certainly forms a strong support for Loeb's theory that calcium is not 
directly essential to rhythmic movement, but only neutralizes the effects 
of sodium. At the same time further investigation is required to overcome 
certain difficulties in the way of the acceptance of this antagonistic action 
of calcium and sodium as the explanation of the necessity of calcium to the 
living organism. 

Therapeutic Uses. — Calcium salts are used in medicine for a number 
of different purposes ; thus the alkaline preparations may be prescribed 
to lessen the acidity of the stomach, and the oxide may be employed as 
a caustic. But these owe their use, not to the calcium ion, but to the 
other part of the molecule — the anion. As a matter of fact, calcium has 
no important effects of its own and is not prescribed for any action which 
it might have on the living tissues. The question has been raised, how- 
ever, whether calcium may not be given therapeutically to supply a 
deficiency of lime in the body. The particular conditions which have 
been treated on this theory are rickets and osteomalacia, in both of 
which there is unquestionably too little lime in the bones, and the treat- 
ment has been thought to be rational, because symptoms similar to 
those of rickets have been induced in young animals whose food con- 
tained too small a proportion of lime. In the case of rickets and os- 
teomalacia, however, there is no reason to suppose that the food is 
deficient in calcium ; in fact, children are said to be more liable to 
rickets when fed on cows' milk than when nursed by the mother, al- 
though the milk of the cow contains more lime. On the other hand, 
patients suffering from rickets absorb lime and excrete it again in ex- 
actly the same way as normal persons, and although their bones con- 
tain unusually small amounts of lime, the other tissues contain rather 
more, or, at any rate, not less than normal. Rickets is not due to a 
lack of lime in the food, therefore, nor in fact in the tissues generally, 
but to some abnormal condition which prevents the lime salts from 
being deposited in the bones, although they are present in abundance 
in the blood. In cases of lime starvation similar symptoms may ap- 
pear, but here the cause is the want of lime, which is not presented in 
sufficient quantities, although the bone-forming cells are ready to de- 
posit it. In this case the other tissues are also deficient in calcium as 
well as the bones. From these considerations it follows that lime salts 
are not likely to be of benefit in rickets (and the same holds true for 
osteomalacia), unless when it is due to lime starvation, a condition 
which is unlikely to arise in the human subject. Experience has 
demonstrated also that the lime salts are quite incapable of improving 
either osteomalacia or rickets. 



574 INORGANIC SALTS, ACIDS AND BASES. 

It has also been proposed to treat with lime cases in which the blood 
seemed less capable of clotting than normally — particularly haemophilia 
and aneurism, and some improvement is said to have occurred in a few 
instances. Here again, however, it would seem to be very improbable 
that the absence of coagulation is due to deficiency in the lime salts, 
for much more is taken in the food than is sufficient for the organism, 
and the pharmacopceial salts are not more easily absorbed than the 
combinations present in food. 1 

Preparations. 

Calcii Chloridum (U. S. P., B. P.) (CaCl 2 ), a white salt with a sharp, saline 
taste, very deliquescent and soluble in water. 0.3-1 G. (5-15 grs ). 

Calcium chloride is the salt which gives the least complicated calcium ac- 
tion, and is consequently seldom used, because, as has been explained, the 
calcium ion is of comparatively little service in therapeutics. It has a strong 
attraction for water and is therefore more irritant than the other chlorides 
of the alkalies and alkaline earths, and ought to be prescribed only in dilute 
solution. It is absorbed with great difficulty, and has been suggested in the 
treatment of some forms of dyspepsia. 

Calx (U. S. P., B. P.) (CaO), unslaked lime, is a corrosive and disinfectant, 
and is changed at once to the hydrate in the presence of water. It differs 
from the caustic alkalies in the insolubility of its hydrate, which therefore 
fails to penetrate deeply and does not spread so widely as potassium and 
sodium hydrates. It is seldom employed alone as a corrosive, but mixed 
with potassium hydrate as Vienna paste (Potassa cum Calce, U. S. P.) has 
had some popularity. 

It is used as a disinfectant where large quantities of organic matter have 
to be rendered harmless, as in epidemics, on battle fields and in the dejec- 
tions of large hospitals. It ought to be mixed with the matter to be disin- 
fected, as thoroughly as possible. Lime possesses the advantage over other 
disinfectants of being cheap and easily procurable in large quantities. 

Calcii Hydras (B. P.), slaked lime (Ca(HO) 2 ), may also be used as a disin- 
fectant. 

Liquor Calcis (U. S. P., B. P.), lime water, is a saturated solution of 
calcium hydrate or slaked lime and contains about 0.17 G. in 100 c.c. (£ gr. 
in 1 oz. B. P.). It is a clear fluid with a saline and feebly caustic taste. 
30-100 c.c. (1-4 fl. oz.). 

Syrupus Calcis (U. S. P.), Liquor Calcis Saccharatus (B. P.), syrup 
of lime, contains calcium hydrate kept in solution in water by sugar, with 
which it is probably combined chemically. The amount of lime contained 
varies greatly, but is much larger than in lime water. The B. P. prepara- 
tion is said to contain nearly 2 per cent, by weight, or 8 grs. to the oz. 1-4 
c.c. (15-60 mins.). 

Linimentum Calcis (U. S. P., B. P.), lime liniment, or Carron oil, con- 
tains equal parts of lime water and olive or linseed oil. 

These preparations owe their activity chiefly to their alkalinity and 
not to the calcium, but differ from the hydrates of the alkalies in their 
insolubility and in their slow absorption. Lime water and the syrup 
are slightly caustic, more especially the latter, and tend to neutralize 

1 Another treatment of aneurism and haemorrhage recently introduced is the admin- 
istration of gelatine by the mouth or hypodermically (100 c.c. of a 1 per cent, solu- 
tion). This is based upon a series of experiments which seemed to indicate that the 
coagulation of the blood is accelerated by gelatine ; but more accurate investigations 
have shown that gelatine has no influence on the rate of coagulation, and no satisfac- 
tory evidence of improvement has been brought forward by clinicians. 






CALCIUM. 575 

the gastric juice. They have an astringent effect in the intestine 
which has not yet been explained, but is probably due to their forming 
an insoluble compound with the surface proteids, in the same way as 
tannic acid, or to their being deposited as the carbonate or phosphate 
and thus protecting the epithelium from irritation. Lime water is 
used in some dyspeptic conditions, especially in vomiting. It is often 
added to milk in intestinal irritation in children and in typhoid fever, 
as it is found that milk thus treated coagulates in finer particles than 
when given alone, and is better digested and less liable to disturb the 
intestine. Lime water or syrup of lime is also used as an intestinal 
astringent in diarrhoea, especially in children. As an antacid in the 
stomach, lime is inferior to magnesia and other alkalies, because it 
tends to delay the evacuation of the contents. Lime water has been 
used in rickets, which seems singularly irrational, for cows' milk con- 
tains a somewhat higher percentage of lime. It has also been sprayed 
against the false membrane of diphtheria, which it is said to dissolve. 
Lime water is not applicable in cases of acid poisoning, as it contains 
much too little of the base to be serviceable, but the syrup may be 
used, or lime shaken up with water (milk of lime). The treatment 
with lime is specially indicated in cases of oxalate poisoning. 

Lime water has been used externally as a protective, mildly astrin- 
gent application to ulcers, and the lime liniment has been largely used 
in the treatment of burns. It derives its name of Carron oil from 
having been used for this purpose in the iron works at Carron. 

Calcii Carbonas Prxcipitatus (U. S. P., B. P.), precipitated chalk (CaC0 3 ). 
1-4 G. (15-60 grs.). 

Creta Prseparata (U. S, P., B. P.), prepared chalk, chalk purified by 
washing and suspension in water (CaC0 3 ). 1-4 G. (15-60 grs.). 

Pulvis Cret^e Compositus (U. S. P.), a mixture of prepared chalk, sugar 
and acacia. 5-10 G. (1-2 drs). 

Pulvis Cret^e Aromaticus (B. P.), aromatic chalk powder, contains 
chalk along with sugar and a number of carminatives belonging to the group 
of volatile oils. 10-60 grs. 

Pulvis Cret,e Aromaticus Cum Opio (B. P.) is a mixture of 39 parts 
of the aromatic powder with one of opium, and therefore contains 2} per 
cent, of opium. 10-40 grs. 

Mistura Cretje (U. S. P.), chalk mixture, is chalk suspended in water 
by means of gums. 15-30 c.c. (£-1 fl. oz.). 

Trochisci Cretse. (U. S. P.), chalk lozenges, flavored with spirit of nutmeg. 

The preparations of the carbonate of lime are used as antacids in 
hyperacidity of the stomach, especially when this is combined with 
a tendency to diarrhoea. The mixture or the aromatic powder B. P., 
is the form generally used, and may be prescribed with opium or with 
other astringents. Chalk has also been used in rickets. 

Externally, prepared chalk is used as a powder to protect irritated 
parts of the skin and occasionally in ulceration ; it is the chief in- 
gredient in most tooth powders. In older treatises on therapeutics, 
great virtues are ascribed to various natural objects which are com- 
posed for the main part of chalk or other salts of lime, and among 



576 INORGANIC SALTS, ACIDS AND BASES. 

which burned bones, coral, coralline, and cuttlefish bone may be men- 
tioned. 

Calcii Phosphas Prsecipitatus (U. S. P.), Calcii Phosphas (B. P.) (Ca 3 (POJ 2 ), 
a white insoluble powder. 0.3-1 G. (5-15 grs.). 

Syrupus Calcii Lactophosphatis (U. S. P., B. P.), a preparation in which a 
soluble double salt of lime is contained in solution. 2-4 c.c. (\-\ fl. dr.). 

A glycerophosphate of calcium has also been advised recently. These 
phosphate preparations have been used in rickets and osteomalacia, and 
in phthisis and other tubercular disease?, but the best authorities are agreed 
that lime salts are of no value in rickets and osteomalacia (see page 573), 
and experience with them in tubercular conditions is not more encouraging. 

Calcii Bromidum (U. S. P.) (CaBr 2 ) has been used as a substitute for the 
more commonly used bromide of potassium, and is administered in the same 
dose. It is more slowly absorbed and therefore inferior to the alkaline bro- 
mides, and is entirely superfluous. 

Calcii Sulphas Exsiccatus (U. S. P.). — Dried calcium sulphate or dried gyp- 
sum contains 95 per cent, of sulphate of calcium (CaSOJ and 5 per cent, of 
water. It is used exclusively to form immovable bandages in surgery (plas- 
ter of Paris bandages). 

Bibliography. 

See Oxalates and Sodium Chloride. 

Jankau. Arch. f. exp. Path. u. Pharm., xxix., p. 237. 

Baudnitz. Ibid., xxxi., p. 343. 

Abel u. Muirhead. Ibid., xxxi., p. 15. 

Badel. Ibid., xxxiii., pp. 79, 90. 

Bey. Ibid., xxxv., p. 295. Deutsch. med. Woch., 1895, p. 569. 

Brubacher. Zts. f. Biol., N. F., ix., p. 516. 

F. Voit. Ibid., xi., p. 325. 

Weiske. Ibid., xiii., p. 421. 

Binger. Journ. of Physiol., iii.-xvi. 

Howell (and pupils). Ibid., xiv., p. 198 ; xvi., p. 476. Amer. Journ. of Phys., v., 
p. 338; vi., p. 181. 

Loeb, Lingle, Lillie, Moore. Amer. Journ. of Phys., iv., p. 265 ; v., pp. 56, 87, 
362; vi., p. 411. 

Loew. Ein natiirliches System der Giftwirkungen, 1893, p. 33. 

Kitasato. Zts. f. Hygiene, iii., p. 404. 

Pfuhl. Ibid., vi., p. 97. 

Binet. Comptes rendus d. FA cad. de Science, ex v., p. 251. 

Bayer. Med. News, 1886, ii., p. 253. 

Vierordt. jSothnagel's Specielle Pathologie und Therapie, vii. 

Hammarsten. Ztschr. f. phys. Chem., xxii., p. 333. 

Strauss. Ztschr. f. klin. Med., xxxi., p. 493. 

Miwa u. Stoeltzner. Ziegler's Beitriige zu Path., xxiv., p. 578. 

XX. BARIUM AND STRONTIUM. 

Barium is the most poisonous of the three common alkaline earths, but 
resembles the others in penetrating with difficulty into the epithelium of the 
alimentary canal, and is therefore absorbed very slowly. It has a charac- 
teristic action on many forms of muscular tissue, resembling closely that of 
veratrine, and the contraction of the frog's muscle under barium is thus 
stronger than normally, and is very greatly prolonged. The frog's heart 
beats more strongly, but more slowly from a similar action on the muscle 
fibres, and the walls of the stomach and intestine are thrown into violent 
contraction from the action of the metal on the unstriated muscle fibre. 
There is some question as to whether the central nervous system is acted on 
in the frog, but in the mammal barium salts injected intravenously cause 
violent tonic and clonic spasms, from their stimulating the spinal cord and 
medulla oblongata. The action on the alimentary canal induces vomiting 
and purging with very active peristalsis. The heart is accelerated, and the 



SULPHIDES AND SULPHUR. 577 

"blood-pressure is enormously increased at first, find then undergoes slow 
undulations for some time. The increased tension may be due to the cardiac 
action in part, but is chiefly to be ascribed to a very marked contraction of 
the muscular walls of the vessels. The frog's heart eventually assumes an 
irregular peristaltic form of contraction and ceases in systole, as in digitalis 
poisoning, and the changes in the mammalian heart also resemble those 
caused by this series. Barium in sufficient quantities finally paralyzes the 
central nervous system. In fatal poisoning in animals, haemorrhages have 
been found in the stomach, intestine, kidney and other organs. 

Barium is quite incapable of replacing calcium in its relations to living 
matter, and accordingly chloride of sodium solutions to which barium chlo- 
ride has been added do not tend to keep the frog's heart active as do those 
containing lime. Some authors hold that barium can replace calcium to an 
imperfect degree in the coagulation of the blood, but this is denied by others. 
Potassium salts tend to neutralize the effect of barium on the heart and mus- 
cles, the relation resembling that which they bear to lime. 

Barium is absorbed slowly from the intestine, and is found to be stored in 
the bones to some extent, and to be excreted in the urine and probably in 
the bowel. 

It has been suggested as a treatment for different forms of tremor, but has 
seldom been used in practical therapeutics. The dioxide of barium of the 
IT. S. P. is used exclusively to form peroxide of hydrogen. 

Bibliography. 

Boehm. Arch. f. exp. Path. u. Pharm., iii. , p. 216. 

Neumann. Pfltiger's Arch., xxxvi., p. 576. 

Bruntonand Cash. Phil. Trans, of Eoy. Soc, 1884, i., p. 223. 

Binet. Comptes rend. d. l'Acad., cxv., p. 251. 

Sommer. Inaug. Diss., Wiirzburg, 1890. 

See also Bibliography of Calcium, Potassium, Rubidium and Caesium. 

Strontium is a comparatively inert substance even when injected directly 
into the blood, resembling calcium in its action in the body as far as is 
known, but being even less poisonous. It contracts the muscles somewhat, 
tends to lessen the dilation of the heart, and prolongs the contraction of 
muscle, though only to a slight extent. It is absorbed very slowly from the 
intestine like the other alkaline earths, and is deposited in small quantities 
in the bones of growing animals, especially when there is a deficiency of lime 
in the food. It is excreted in small quantities by the urine, and probably 
by the bowel. Strontium salts have been used to a limited extent in thera- 
peutics, not for the effect of the strontium ion, but for the bromide, iodide 
or salicylate effects of its salts. In view of the fact that the strontium salts 
are more slowly absorbed than the corresponding ones of sodium and potas- 
sium, there would seem to be good grounds for abandoning their use. 

Preparations. 
IL S. P. — Strontii Bromidum (SrBr 2 + 6H 2 0), 1-4 G. (30-60 grs.). 
Strontii Iodidum (Srl 2 + 611,0), 0.3-1 G. (5-15 grs.). 
Strontii Lactas (Sr(C 3 H 5 3 ) 2 + 3H 2 0), 1-2 G. (15-30 grs.). 

Bibliography. 

See Calcium, Barium. 

Wood. Am. Jour, of Physiol., i., p. 83. 

XXI. SULPHIDES AND SULPHUR. 

The ordinary sulphides of the alkalies are of little importance in 
themselves, as they are seldom used in therapeutics. The effect of 
37 



578 INORGANIC SALTS, ACIDS AND BASKS. 

hydrosulphuric acid, however, apart from its local irritant action, is due 
to the sulphide which it forms in the blood, and the study of this 
powerful poison therefore involves a preliminary examination of the 
effects of the sulphides. Again, sulphur is in itself inert, but is 
changed to sulphides and hydrosulphuric acid in the alimentary canal, 
and the effects induced by its administration are due to these bodies, 
and not to the original element. 

Action. — The sulphides are very weak salts, for even carbonic acid is 
capable of liberating hydrosulphuric acid, and wherever they come in con- 
tact with it in quantity, there is a tendency to form free acid, which acts as 
a powerful local irritant ; it is not impossible that the sulphides have an 
irritant effect of themselves in addition to that of the hydrosulphuric acid. 
The sulphides accordingly act as irritants in the stomach and bowel, and in 
the latter induce increased peristalsis and purgation. When injected sub- 
cutaneously in the frog, sodium sulphide causes a narcotic condition from 
depression of the central nervous system, and in sufficient quantities weakens 
the skeletal muscle and the heart, which continues to beat after complete 
paralysis has been obtained, but eventually ceases in diastole. Harnack has 
recently shown that after the narcosis has lasted for some time, a new con- 
dition follows, if only small quantities have been given, and especially if the 
frog is healthy and is kept cool. This consists in an enormous increase in 
the reflex irritability, which induces convulsions resembling those of strych- 
nine poisoning in their general character, but differing from them in lasting 
continuously for weeks or even months at a time. The animal lies in an ex- 
tended and tense condition throughout, and passes into complete opisthotonos 
on being touched. 

Sulphides injected intravenously in mammals induce violent convulsions, 
which seem to be of cerebral origin, for they do not occur in the hind limbs 
when the spinal cord is cut. The respiration is at first accelerated and later 
dyspnceic and finally ceases, this along with the paralysis of the vaso-motor 
centre being the cause of death. The heart does not seem to be seriously 
affected except indirectly through the failure of the respiration and the fall 
of the blood-pressure. 

Sulphide solutions added to drawn blood reduce the oxyhemoglobin at 
once, and give the blood a dark venous color. At the same time a compound 
of sulphide and haemoglobin is formed, the chemistry of which is still very 
obscure, but which would seem to be more nearly related to methaemoglobin 
than to haemoglobin. It is known as sulpho-haemoglobin or as sulpho-met- 
hsemoglobin, and gives the blood a greenish color when a thin layer is ex- 
amined, while a thicker layer is dark red-brown. This sulpho-hsemoglobin 
possesses a characteristic spectrum, marked by a dark line in the red to the 
left of the D line. Larger quantities give an olive-green color to the blood, 
and the spectrum of sulpho-hsemoglobin disappears. When sulphides are 
injected into frogs, and more especially when sulphuretted hydrogen is in- 
haled, the blood gives the characteristic spectrum during life, but this does 
not seem to be the case in mammals, although sulpho-haemoglobin is formed 
soon after death. The blood changes are not the cause of death in poison- 
ing, as was formerly supposed, but the direct action of the sulphides on the 
central nervous system. 

Sulphides absorbed into the blood are rapidly oxidized, and are excreted in 
the urine in the form of sulphates and of organic sulphur compounds of un- 
known constitution. Small quantities escape by the lungs, and give the 
breath the disagreeable odor of sulphuretted hydrogen, and according to 
some authorities, some is excreted in this form in the perspiration. 

The sulphides dissolve the horny epidermis and hair very readily when 
they are applied to the skin. If the application is continued, some irritation 
and redness is produced. 



SULPHIDES AND SULPHUR. 579 

Hydrosulphuric Acid (sulphuretted hydrogen, hydrogen sulphide (H 2 S)) 
differs from the sulphides in being a gas, and in its strong irritant properties, 
which it shares with other acids (see page 559). It has not infrequently 
given rise to poisoning, as it is formed in large quantities in the course of the 
putrefaction of sulphur compounds, such as proteids. Sewer gas often con- 
tains it in quantity, and workmen employed in cleansing sewers or cesspools 
have often suffered from its effects. When inhaled in concentrated form it 
is almost immediately fatal, the patient losing consciousness at once, and the 
respiration ceasing after a few seconds. In smaller quantities it causes im- 
mediate unconsciousness, lasting for several hours and then passing into fatal 
coma, which is often interrupted by violent convulsions. In both of these 
forms the symptoms are due to the direct action of the sulphides on the brain 
and medulla oblongata. Persons exposed to a very dilute vapor of sulphur- 
etted hydrogen suffer from local irritation of the eyes, nose and throat, indi- 
cated by pain and congestion of the conjunctiva, sneezing, dryness and sore- 
ness of the mouth and throat, and a reflex increase in the secretion of tears, 
saliva and mucus. Headache, dulness, giddiness and loss of energy are com- 
plained of; the symptoms frequently appear only some time after the ex- 
posure to the poison. According to Lehmann, death in animals exposed to 
these dilute fumes is due in part to oedema of the lungs caused by the local 
irritant action. He found that one part of hydrosulphuric acid in 5,000 of 
air was sufficient to induce symptoms in man, and that an atmosphere con- 
taining one part in 2,000 could be respired for only a short time, and gave 
rise to alarming symptoms ; he supposes that about one part of hydrosul- 
phuric acid in 1,000 parts of air is sufficient to poison man fatally in a very 
short time. 

The poisonous effect of sulphuretted hydrogen is due in part to its local 
irritant action, in part to its directly affecting the central nervous system. 
The changes in the blood occur during life only after very concentrated gas 
is inhaled, although they may indicate the poison after death from more 
dilute vapor, for the tissues in general tend to assume a green color sooner 
after hydrosulphuric acid poisoning than in the course of ordinary putrefaction. 

Hydrogen sulphide is destructive to most forms of life, even when present 
in comparatively small amount. Even the microbes of putrefaction, which 
produce it themselves, are eventually killed by this gas, unless it escapes 
freely. 

Preparations. 

Potassa Sulphurata (U. S. P., B. P.), liver of sulphur (Hepar Sulphuris), 
is a mixture of polysulphides and thiosulphates, often containing sulphate 
of potassium. The greater part is formed of potassium trisulphide (K 2 S 3 ) 
and of potassium thiosulphate (K 2 S 2 3 ). It is soluble in water and possesses 
an unpleasant saline taste, and an odor of hydrogen sulphide, which is formed 
by its decomposition in water. 

Calx Sulphurata (U. S. P., B. P.), sulphurated lime, is another impure 
preparation containing at least 60 per cent, of calcium monosulphide (CaS) 
(50 per cent. B. P.), with some calcium sulphate and charcoal. It forms a 
grayish powder, insoluble in water, and gives off hydrogen sulphide. 0.015 
-0.06 G. (1-1 gr.). 

These preparations are seldom used internally, and, in fact, the sulphur- 
ated potassium has been found to be a dangerous poison, from the hydrogen 
sulphide given off by it in the bowel acting both locally and after absorption. 

Sulphurated potassium is used to a very limited extent as an external appli- 
cation in certain skin diseases, particularly in acne, and to destroy skin 
parasites, such as that of scabies. It is used as an ointment (1 part to 10 
parts), and is somewhat irritant. 

Sulphurated lime is used occasionally to remove hair and horny excres- 
cences, both of which it renders soft and gelatinous, but its frequent use is 
liable to cause irritation. 



580 INORGANIC SALTS, ACIDS AND BASES. 

Hydrogen sulphide has been used in the treatment of pulmonary phthisis, 
the gas being applied by the rectum, but the treatment was followed in sev- 
eral cases by serious symptoms of poisoning, and has not been shown to be 
beneficial. Very small quantities only escape by the lungs. 

Many mineral springs contain hydrogen sulphide in small amount, and 
these have obtained wide celebrity in the treatment of various chronic res- 
piratory and skin diseases and in syphilis, gout, rheumatism and chronic 
metallic poisoning (lead, mercury). Most of these springs are hot, and it is 
open to question whether the small amount of the gas contained in the 
water is of any efficacy, and whether the heat of the water and the hygienic 
conditions are not the true cause of the improvement observed in these cases. 
Sulphur baths are also formed artificially by the addition of sulphurated 
potassium (2-8 oz.) to an ordinary hot bath ; a small quantity of acid is some- 
times added, in order to free the hydrogen sulphide more rapidly. 

Sulphur is in itself an inert body, but while much the greater portion 
escapes in the stools unchanged when it is swallowed, some of it forms 
sulphides in the alkaline fluids of the intestine, and these cause irrita- 
tion, increased peristalsis and mild purgation ; in large quantities, it 
has caused in some instances more severe symptoms with bloody evac- 
uations. The sulphides form some hydrogen sulphide, which gives 
rise to eructation. Some 10-20 per cent, of the sulphur taken by the 
mouth is absorbed as sulphide, which is excreted to a small extent by the 
lungs, giving the characteristic disagreeable odor to the breath, and to 
a much larger extent by the urine as sulphates and in organic combi- 
nation. In one experiment, Presch found the urea of the urine con- 
siderably increased (10 per cent.) under sulphur, and Umbach found 
it increased by pure calcium sulphide ; whether, as this would suggest, 
the sulphides augment the nitrogenous waste as a general rule, can only 
be determined by further experiment. 

Applied to the skin in ointment, sulphur appears to be formed in 
part to sulphide, particularly if some alkali be added. 

Preparations. 

Sulphur Sublimatum (U. S. P., B. P.), Flowers of Sulphur, sublimed sul- 
phur. 

Sulphur Lotum (U. S. P.), washed Flowers of Sulphur, is prepared by 
washing the sublimed sulphur with water and ammonia. These prepara- 
tions form fine yellow powders insoluble in water and very slightly soluble 
in alcohol. 1-4 G. (15-60 grs.) in powder or sometimes in tablets. 

Sulphur Prsecipitatum (U. S. P., B. P.), Milk of Sulphur, is prepared from 
sulphide of calcium by precipitation and forms a fine, almost white powder 
without odor or taste, insoluble in water, and only very slightly soluble in 
alcohol. 1-4 G. (15-60 grs.). 

TJnguentum Sulphuris (U. S. P., B. P.), formed from sublimed sulphur, 
which is also contained in the Compound Liquorice Powder. 

Trochiscus Sulphuris (B. P.) contains 5 grs. of sulphur. 

Confectio Sulphuris (B. P.), 60-120 grs. 

Thilanin (non-official) is a mixture of lanolin and sulphur containing about 
3 per cent, of the latter, and has been proposed as a substitute for the oint- 
ment. 

Crude sublimed sulphur often contains arsenic and other impurities, and 
ought not to be used in therapeutics. The milk of sulphur is in a finer 
state of division than the flowers, and is said to be a somewhat more active 
aperient. 






CHARCOAL. 581 

Sulphur is used as an aperient powder, and may be added, to rhu- 
barb or magnesia for this purpose ; it causes a soft, formed stool, and 
seldom induces more than one evacuation. It is prescribed for chil- 
dren, and in cases of haemorrhoids, in which it is often very beneficial, 
not owing to any specific effect on the haemorrhoids, but because it 
renders the stool softer and less liable to cause irritation mechanically. 

Sulphur has been advised in a variety of constitutional diseases and 
in chlorosis, skin and joint affections, but it is impossible to state at 
present whether it has any effect in these apart from its improving the 
condition of the intestine. 

Sulphur ointment has been used in some skin diseases, particularly 
in scabies, but has been supplanted to a large extent by the balsam of 
Peru. It has been applied in powder to diphtheritic membranes. 

Bibliography of Sulphides and Sulphur. 

Kaufmann u. Rosenthal. Arch, f . Anat. u. Phys. , 1865, p. 659. 

Leivin. Virchow's Arch., lxxiv., p. 220. 

Lekmann. Arch. f. Hygiene, xiv., p. 135. 

Pohl. Arch. f. exp. Path. u. Pharm., xxii., p. 1. 

Harnack. Ibid., xxxiv., p. 156. Ztschr. f. phys. Chem., xxvi., p. 558. 

Regensburger. Ztschr. f. Biol., xii., p. 479. 

Presch. Virchow's Arch., cxix., p. 148. 

UschinsJcy. Zts. f. phys. Chem., xvii., p. 220. 

Araki. Ibid., xiv., p. 412. 

Binet. Trav. des Lab. de Ther. exp. de Geneve, ii., p. 242. 

Umbach. Arch. f. exp. Path. u. Pharm., xxi., p. 166. 

Meyer. Ibid., xli., p. 325. 

XXII. CHARCOAL. 

Charcoal, like spongy platinum and other porous bodies, possesses the 
property of accumulating gases in its interstices and thus ordinarily contains 
considerable quantities of oxygen. When brought into contact with decom- 
posing matter, the oxygen is released and hastens the oxidation of the putre- 
fying mass, while the gases arising from the bacterial action are absorbed by 
the charcoal which thus acts as a deodorant. It has no direct action on the 
microbes of putrefaction, but may by introducing oxygen favor the develop- 
ment of the aerobic organisms at the expense of the anaerobic. Besides 
gases, charcoal also absorbs many colloid bodies, such as the coloring matter 
of plants and proteids, and when solutions of salts are filtered through layers 
of it, they often undergo more or less dissociation, the base passing into the 
filtrate, while the acid remains in the charcoal, or vice versa. 

Animal charcoal appears to possess no advantages over wood charcoal, 
and they both act when moist almost as efficiently as in the dry state. 

Charcoal has no appreciable effect on the economy, apart from its lessen- 
ing the eructation of gas and the flatulence in some cases. It passes through 
the stomach and intestine unabsorbed, and may in rare cases cause some 
mechanical irritation and increased movement. Charcoal given in a state of 
suspension to animals is said to have been found in the epithelial cells of the 
intestine and even in the blood vessels, but does not have any effect attribut- 
able to its absorption in man. (Wild. Med. Chronicle, 1896.) 

Preparations. 

Carbo Animalis (U. S. P.), animal charcoal, bone-black, prepared from 
bone. 

Carbo Animalis Purificatus (U. S. P.) is prepared by boiling bone-black 
with hydrochloric acid in order to remove the lime and other impurities. 



582 INORGANIC SALTS, ACIDS AND BASKS. 

Carbo Ligni (U. S. P., B. P.) — Charcoal prepared from soft wood and 
finely powdered. 

Charcoal is used internally to remove the gases in flatulence and dyspep- 
sia, and is prescribed in powder or in the form of charcoal lozenges. It may 
be given in any quantity, but is most commonly prescribed in 4-8 G. ((50- 
120 grs.) doses. It is employed externally as a deodorant in cases of foul 
ulcers, cancerous sores, or malodorous secretions from any source ; for this 
purpose it is added to poultices or used dry in bags of fine cloth. 

XXIII. BORACIC ACID AND BORAX. 

Boracic or boric acid (B(OH) 3 ) is a very weak acid, and it is doubt- 
ful whether the hydrogen ions or acidity play any part in its action, or 
whether the whole is not to be referred to the rest of the molecule. 
The ordinary sodium compound, borax, Na 2 B 4 7 , is stated by some 
authors to be equally active, but is alkaline in reaction, so that the 
exact relative importance of the two ions of boric acid cannot be de- 
termined. 

Action. — Boracic acid and borax are only feebly toxic, but large 
quantities taken by the mouth cause gastric and intestinal irritation, as 
is evidenced by vomiting and purging, and even smaller amounts are 
said to act as mild aperients in some cases. In animals muscular weak- 
ness and collapse, and, it is said, nephritis and albuminuria have been 
elicited by the injection of poisonous doses. Moderate doses are with- 
out effect on the metabolism, but larger quantities (5-10 G. per day in 
dogs) increase the nitrogen excretion in the urine. In ordinary amounts 
borax does not affect the digestion and assimilation of food, but larger 
doses retard the proteolytic processes, and increase the bulk of the faeces 
by retarding the absorption of the proteids and fats. Both borax and 
boracic acid are rapidly absorbed by the bowel, and do not affect the 
intestinal putrefaction. 

Boracic acid has been widely used as an antiseptic dressing, and a 
number of cases of serious poisoning have been recorded from its ab- 
sorption. The symptoms arose in part from the alimentary canal, 
uneasiness in the abdomen, vomiting, diarrhoea, dryness of the throat 
and difficulty in swallowing ; sleeplessness, great muscular weakness 
and depression, dimness of sight and headache were also complained 
of, and in severe cases collapse and death followed. The prolonged 
use of boracic acid, internally or externally, has repeatedly led to scaly 
skin diseases, eczema and psoriasis. Fere* ascribes these to the absence 
of the oily secretions of the glands of the skin, and has observed that 
the hair becomes brittle and breaks off short, causing alopecia of the 
scalp and also of other parts of the body. Papular eruptions and 
local oedemas and swelling of the skin appear, and a dark line on the 
gums, similar to that seen in lead poisoning, is stated to occur along 
with irritation of the mouth. These skin affections appear also when 
borax is used in large quantities as an antiseptic dressing. 

Boracic acid and borax are excreted in the urine for the most part, 
to a smaller extent in the perspiration, saliva, and intestinal secretions. 
They disappear from the body within 24 hours of their ingestion. It 



BOBACIC ACID AND BOBAX. 583 

is sometimes stated that the urine is increased by borax, but this is 
not borne out by experiment, and Chittenden and Gies found it actu- 
ally diminished in amount ; the reaction becomes alkaline after suffi- 
cient amounts of borax, as after any other alkaline preparation. Bor- 
acic acid and borax have some antiseptic power, for in 2 J per cent, 
solution almost all forms of bacilli stop growing ; but they are not 
destroyed, even the delicate anthrax bacilli being found capable of 
further growth after exposure to a 4 per cent, solution for 24 hours. 
Boracic acid is therefore valueless as a disinfectant, but has been used 
as an antiseptic dressing ; it has the advantage over many other anti- 
septics of inducing very little irritation and of being only slightly 
poisonous, but experience has shown that it cannot be used with im- 
punity in very large quantities. 

Preparations. 

Acidum Boricum (U. S. P., B. P.), Boric or Boracic Acid (H 3 B0 3 ), color- 
less crystals, with a faintly bitter taste, soluble to about four per cent, in 
water, more so in alcohol and glycerin. 0.3-1 G. (5-15 grs.). 

Glyceritum Boroglycerini (U. S. P.), Glycerinum Acidi Borici (B. P.). Boro- 
glycerin is a compound formed by heating boric acid in glycerin, and the 
official glyceritum or glycerinnm contains this dissolved in glycerin, about 
31 parts of boric acid being used to form 100 parts. 

Unguentum Acidi Borici (B. P.), 10 per cent. 

Sodii Boras (U. S. P.), Borax (B. P.), Borax (Na 2 B,0 7 + 10H 2 O) forms 
colorless crystals with a sweetish alkaline taste. It is soluble in water (16 
parts) to which it gives an alkaline reaction. 0.3-1.3 G. (5-20 grs.). 

Glycerinum Boracis (B. P.) (1 in 6). 

Mel Boracis (B. P.). 

Boracic acid has been used as a surgical antiseptic in solution (four 
per cent.), ointment, or lint, and the solution of the acid or of borax 
is also used as a wash in aphthe and other forms of irritation of the 
mouth. Boracic acid solution has been given internally in dilute 
watery solution as a genito-urinary disinfectant, has also been injected 
into the bladder, and is frequently used in ophthalmic surgery, as be- 
ing less irritant to the eye than the more powerful antiseptics. In 
internal medicine the acid and the salt have been used in epilepsy, and 
also in the hope of dissolving uric acid calculi, but have not been 
shown to be efficient for either purpose. Boracic acid and borax are 
sometimes added to milk or other food as preservatives, and it has 
been much discussed whether the habitual use of such preserved foods 
is likely to prove deleterious to the health. The general result of the 
investigations is that while no preservative should be added to food 
unless it is absolutely unavoidable, boric acid in moderate quantities 
is not prejudicial to persons in ordinary health and in fact is less liable 
to derange the digestion than nitrate of potassium, which has been 
used as a preservative from time immemorial. Foods preserved with 
boracic acid should not be used by delicate individuals or by children 
however, and the quantity of the acid used must be strictly limited. 



584 INORGANIC SALTS, ACIDS AND BASES. 

Bibliography. 

Neumann, Arch. f. exp. Path. u. Pharra., xiv., p. 149. 

Forsler. Arch. f. Hygiene, ii., p. 75. 

Jaenicke. Therapeut. Monatsh., 1891, p. 477. 

Johnson. Jahresber. tiber Thierchemie, 1885, p. 235. 

Fere. Semaine Medical, 1894. 

Chittenden and Gies. Am. Journ. of Phys., i., p. 1. 

Wild. Lancet, 1899, i., p. 23. 

Liebreich. Vierteljahrsch. f. ger. Med., 1900, xviii., p. 83. 

Lange. Arch. f. Hygiene, xl., p. 143. 

Kister. Ztschr. f. Hygiene, xxxvii., p. 225. 

Tunnicliffe and Rosenheim. Journ. of Hygiene, i., p. 168. 

Vaughan and Veenboer. Amer. Medicine, 1902, Mar. 15th. 

XXIV. CARBONIC ACID. 

Carbonic acid is contained in considerable quantity in many thera- 
peutic preparations, notably in the effervescent cathartics and antacids, 
and also in many beverages, such as soda water, potash water, cham- 
pagne and other sparkling wines. In some of these it is formed by 
the action of an acid such as citric or tartaric acid on carbonates, in 
others it is liberated in the course of fermentation, while in the artifi- 
cial aerated waters it is forced into solution under high pressure. The 
last are therefore simple solutions of carbonic acid, while in the others 
more powerful agencies — cathartic salts or alcohol — are contained in 
addition. 

Carbonic acid has a weak irritating action when applied in quantity; 
thus in baths charged with carbonic acid, a slight reddening of the 
skin has been observed, and some irritation and prickling of denuded 
surfaces is produced ; a stream of carbonic acid directed against a 
wound or burn causes considerable heat and pain. Pure carbonic acid 
gas causes spasm of the glottis when inhaled, and even when it is much 
diluted, some irritation in the respiratory passages may follow at first. 
Solutions of carbonic acid induce reddening of the mucous membrane 
of the mouth and stomach, and are very rapidly absorbed, owing to 
the congestion and increased blood flow in the stomach wall which 
follows their administration. Much of the carbonic acid is thrown up 
by eructation, but some of it is absorbed and is excreted by the lungs. 
The absorbed acid has no effect on the organism, but the slight irrita- 
tion of the stomach may cause increased appetite and a feeling of well- 
being. The rapid absorption of the water in which it is dissolved is 
followed by an augmented secretion of urine, and the carbonic acid 
waters are therefore used in preference to ordinary waters, where a 
rapid flushing of the tissues and a profuse secretion of urine is de- 
sired. In addition, the slight irritation of the mouth and stomach 
renders them more acceptable than ordinary waters in fever and in 
other diseases accompanied by intense thirst ; a mixture of milk and 
aerated water is often very grateful. The presence of carbonic acid 
in the sparkling wines leads to the rapid absorption of the alcohol 
also, and this action on the stomach may explain their being more ex- 
hilarating than other wines containing an equal amount of alcohol. 



CARB ONIC A CID. 585 

The slight irritant effect of carbonic acid in the stomach has proved 
of benefit in some forms of gastric catarrh, such as that following 
alcoholic excess. Carbonic acid waters are also useful in the vomiting 
of pregnancy and in seasickness. 

The prolonged application of carbonic acid to the mucous mem- 
branes leads to local anaesthesia, and numbing of the skin is also stated 
to occur under similar treatment. 

Carbonic acid is absorbed from all the mucous membranes, from the 
skin and from the lungs. The gas has no effect after absorption ex- 
cept when inhaled, however, as when absorbed in any other way it 
is at once excreted by the lungs, and the amount absorbed never alters 
appreciably the normal percentage of carbonic acid in the blood. 

When carbonic acid is inhaled unmixed with oxygen, it induces asphyxia, 
partly from a specific action which it exerts on the central nervous system, 
but chiefly from the absence of oxygen. Its effects are therefore very 
similar to those of any indifferent gas, such as hydrogen or nitrogen, and 
the symptoms are those of ordinary asphyxia. When, however, carbonic 
acid is inhaled mixed with a sufficient amount of oxygen, the specific 
effects of the gas are observed without any asphyxia. The symptoms are 
those of transient stimulation and subsequent depression of the central 
nervous system and heart. The first stage is marked by a very short period 
of psychical exaltation, with deep respirations, a slight rise in the blood- 
pressure and a moderately slow pulse. Very soon, however, unconscious- 
ness, loss of the spontaneous movements, and later of the spinal reflexes 
follow, the respiration becomes somewhat slower and shallower, the pulse 
continues slow and the heart is weaker. If the inhalation be continued the 
respiration fails, the heart continuing to beat for a short time, though weakly. 
The symptoms of the first stage seem to be due to a direct stimulant action 
on the cerebrum and on the vagus, vaso-motor and respiratory centres, while 
the second stage resembles that induced by the ordinary anaesthetics, and 
is evidently caused by depression of the central nervous system and of the 
heart muscle. In fact a mixture of carbonic acid and air has been used as 
an anaesthetic in one or two surgical operations. Death from carbonic acid 
poisoning is not preceded by convulsions, those observed in ordinary as- 
phyxia being due to the absence of oxygen, and not to the excess of car- 
bonic acid ; it is still undecided by which of these factors the increased per- 
istalsis seen in suffocation is caused. In well diluted vapor the symptoms 
of exaltation alone are observed, no anaesthesia following. 

Carbonic acid in excess acts as a poison to other organs besides the central 
nervous system and the heart, although this effect is not seen in mammals. 
Frog's muscle loses its irritability rapidly, the ciliated epithelium ceases 
movement, and the motor nerves, after a short period of increased excita- 
bility, are paralyzed by exposure to an atmosphere of carbonic acid. The 
blood assumes the venous color when shaken with the gas, and prolonged 
contact produces acid haematin, as does any other acid. 

Carbonic acid probably acts as a general poison to the protoplasm in mam- 
mals, apart from the effects on the central nervous system, for the combustion 
in the tissues is lessened to an extraordinary degree, as is evidenced by the 
very small amount of oxygen absorbed. 

Compressed carbonic acid gas absorbs much heat in expanding, and a 
stream of it directed against the skin induces intense cold and might there- 
fore be used to induce local anaesthesia. (See Ether, page 182.) 

The inhalation of diluted carbonic acid has been recommended in various 
pulmonary affections, such as phthisis and bronchitis, but is of very doubt- 
ful benefit. 



586 INORGANIC SALTS, ACIDS AND BASKS. 

Mineral waters containing large quantities of carbonic acid in solution are 
often recommended as baths in various chronic diseases, such as rheumatism. 
The effects may be due to the carbonic acid in part, but these waters also 
contain salts in solution. 

Bibliography. 

P. Bert. Lecons sur la Respiration. Paris, 1870. 
Quincke. Arch. f. exp. Path. u. Pharm., vii., p. 101. 
Bunge. Ibid., x., p. 332. 

Friedlander u. Herter. Zts. f. phys. Chem. , ii. , p. 99. 
Loevjy. Pfl tiger's Arch., xlvii., p. 601. 

XXV. CHLORINE AND BROMINE. 

Chlorine and bromine resemble each other closely in the effects 
which they induce in all forms of living matter. These may be ex- 
plained in part by their replacing hydrogen in its combinations in the 
proteids and forming hydrochloric or hydrobromic acid with the hydro- 
gen set free, in part by their combining with the hydrogen of water 
and thus liberating nascent oxygen, which then acts on the tissues. 
The latter process is believed to account for the fact that chlorine is a 
much more powerful disinfectant in moist air than in dry. In the 
higher organisms all of these reactions probably occur together. 

Action. — Chlorine and bromine are general protoplasm poisons ; 
thus 3 parts of chlorine in 1,000 parts of moist air are sufficient to 
destroy the spores of most bacteria in the course of three hours, and 
the infusoria and the higher plants have been shown to be equally 
susceptible to the influence of the gas. Even smaller quantities of 
bromine are disinfectant. 

In the higher animals and in man chlorine and bromine act as 
irritants. Thus chlorine water (a saturated solution of chlorine in 
water) induces irritation and redness of the skin, and even blistering, 
when the gas is prevented from escaping. Bromine also causes very 
painful blistering, the fumes penetrating more deeply into the tissues 
than the non-volatile irritants, and causing more widespread irritation. 
Bromine or chlorine water, when swallowed, elicits intense inflamma- 
tion and corrosion of the mouth, throat and stomach, with collapse and 
all the ordinary effects of gastric irritation. Air containing even a 
very small proportion of chlorine irritates the eyes, nose, larynx and 
the deeper respiratory passages, the bronchi and lungs seeming more 
susceptible than the rest of the tract, for bronchitis, pulmonary con- 
gestion and haemorrhages, coughing and pain in the thorax are induced 
by quantities that cause little or no irritation of the mouth and nose. 
Lehmann found that one volume of chlorine or bromine vapor in one 
million parts of air cause some irritation, but no serious results, but 
that ten volumes in the same amount of air inhaled for some time, 
cause haemorrhage and inflammation of the lungs, severe bronchitis and 
other similar effects. After fatal poisoning from the inhalation of 
bromine, he observed marked irritation of the gastric mucous mem- 
brane, while this symptom was absent after chlorine. Another point 
in which bromine differs from chlorine is in its powerful action on the 



CHLORINE AND BROMINE. 587 

hair, which is rendered soft and gelatinous, and eventually removed 
entirely by exposure for some time to the vapor. 

These symptoms of chlorine and bromine poisoning are caused by their 
local action only, and are so severe that they might conceal those induced 
by the effects of the halogens after absorption. The greater proportion of 
the poisons is undoubtedly changed to hydrochloric and hydrobromic acids, 
and these again to chlorides and bromides in the course of absorption. But 
it seems possible that some may form proteid compounds in the body (as 
happens in the test-tube), and that these may have some action. As a mat- 
ter of fact both chlorine and bromine are stated to have a narcotic effect on 
the brain quite apart from their local effects, but nothing further is known 
of their action in the tissues. Herxheimer has recently described four cases 
of what he considers chronic chlorine poisoning in workmen exposed to the 
gas in manufactories ; the chief symptoms were acne of the skin, anaemia, 
sleeplessness and confusion. But it is not yet established that these cases 
were due to chlorine itself, for Bettmann found a very similar condition in 
workmen in a chemical factory in which there was no reason to believe that 
chlorine was evolved ; he is inclined to attribute it to some unknown organic 
compound containing chlorine. 

Preparations. 

Aqua Chlori (U. S. P.), chlorine water, contains at least 4 parts of the gas 
in 1,000 parts of water. It is a clear, greenish liquid with the suffocating 
odor of chlorine and is liable to form hydrochloric acid, especially when 
exposed to the air and sunlight. It ought therefore to be freshly prepared 
when the full strength is required. 

Calx Chlorata (U. S. P.), Calx Chlorinata (B. P.), chlorinated lime, bleach- 
ing powder, sometimes erroneously called chloride of lime, is a compound 
formed by the action of chlorine on lime. It consists of a mixture of cal- 
cium hypochlorite (Ca(C10) 2 ), calcium chloride (CaCl 2 ), lime and water. 
The hypochlorite is very unstable and gives off chlorine in air, and espe- 
cially in the presence of an acid. Strong acids also free the hydrochloric 
acid of the chloride, and this is decomposed by the hypochlorite into chlorine 
and water. Chlorinated lime forms a white or grayish-white powder, with 
the odor of chlorine. It is only partially soluble in water, and must contain 
not less than 35 per cent, of available chlorine, U. S. P. ; 33 per cent. B. P. 

Liquor Calcis Chlorinatse (B. P.). — The solution should yield about 3 per 
cent, of chlorine. 

Liquor Sodse Chloratse (U. S. P.), Liquor Sodse Chlorinatse (B. P.), solution 
of chlorinated soda, Labarraque's solution or Javelle's solution, is formed 
from chlorinated lime and contains hypochlorite of soda (NaCIO) and 
chloride of soda. Like the corresponding lime salt, it has the odor of 
chlorine, and bleaches vegetable colors. It must contain at least 2.6 per 
cent, by weight of available chlorine, U. S. P.; 2.5 per cent., B. P. 10-20 
mins. 

Bromum (U. S. P.), bromine, a heavy, brownish-red liquid evolving a yel- 
low-red, very irritant vapor. 

Chlorine was formerly used internally in infectious disease, but this 
has been entirely abandoned, since it has been recognized that it is 
much more poisonous to the higher animals than to the micro-organ- 
isms. The inhalation of chlorine in phthisis has also fallen into dis- 
use for the same reason. Chlorine water and the solution of chlori- 
nated soda are still occasionally used as antiseptic, deodorant solutions 
in the treatment of foul sores, and, more rarely, to disinfect the hands 



588 INORGANIC SALTS, ACIDS AND BASES. 

before operation ; both preparations are very irritant, however. Chlo- 
rine water much diluted has been used as a gargle, as a vaginal injec- 
tion and for other similar purposes. 

The chlorine preparations are chiefly used to disinfect faeces, urinals 
and to a less extent rooms and houses ; for this purpose chlorinated 
lime is the most suitable, especially when acid is added to it in excess. 
The room ought to be hermetically sealed, and the fumes are of no 
value as disinfectants unless they are present in such quantity as to 
render the air quite irrespirable. They have the disadvantage that 
they bleach most of the colors used in dyeing, and fail to penetrate in 
sufficient quantity into the clothing, which they also corrode to some 
extent. Chlorinated lime exposed in the sick-room merely serves as 
a deodorant, and has no disinfectant value, but has the disadvantage 
of giving a false feeling of security like other similar measures. 
Chlorine seems inferior to sulphurous acid anhydride, and still more 
so to formalin as a disinfectant, not from its being weaker in action, 
but because it is more difficult to apply in sufficient quantity. Chlo- 
rinated lime can, however, be applied in urinals and closets, where 
both these disinfectants are unavailable. Here it acts again as a de- 
odorant, while its disinfectant value is smaller. 

Bromine is also powerfully disinfectant, but has not been used prac- 
tically for this purpose in recent years. It is occasionally employed 
as a corrosive, e. g., in disease of the os uteri. 

In Poisoning with chlorine taken by the mouth, alkalies are advised 
with the view of neutralizing the acid formed, and narcotics may be 
necessary for the pain. In cases of poisoning by inhalation, steam 
may be inhaled to lessen the irritation, and ammonia has been advised, 
but is itself irritant. In corrosion of the skin with bromine, one half 
per cent, carbolic acid has been applied with success, it is said, the 
bromine being precipitated as bromphenol. Vapor of carbolic acid 
has also been inhaled in bromine irritation of the nose and throat. 

Bibliography. 

Binz. Arch. f. exp. Path. u. Pharm., xxxiv., p. 194. 
Lehmann. Arch. f. Hygiene, vii., p. 231 ; xxxiv., p. 308. 
Fischer u. Proskauer. Mittheil. a. d. Gesundheitsamt, ii., p. 228. 
Cash. Eeports of Brit. Local Gov. Board, 1886. 
Herxheimer. Munch, med. Woch., 1899, No. 9. 
Bettmann. Deutsch. med. Wochenschrift, 1901, July 4. 



XXVI. OXYGEN. 

Ever since the discovery of the relation of oxygen to the respiration, at- 
tempts have been made to use it in therapeutics, by inhaling the gas pure or 
mixed with air, or by spending a certain time each day in chambers of com- 
pressed air. It was expected that by these means a larger amount of oxygen 
would be absorbed, and a more active combustion in the tissues would be 
induced. The absorption of oxygen by the lungs does not depend on the 
partial pressure of the oxygen, however, but on its affinity for the reduced 
haemoglobin of the corpuscles. It is true that the oxygen dissolved in the 



OXYGEN. 589 

plasma is increased by a great rise in the barometric pressure, or by 
inhaling pure oxygen, but this dissolved oxygen is trifling in amount com- 
pared with that in combination with the haemoglobin. Under ordinary con- 
ditions, then, the air is sufficient to oxidize almost all the reduced haemo- 
globin passing through the lungs, and oxygen lessens but slightly the small 
proportion that escapes by the pulmonary veins unoxidized. As far as the 
tissues are concerned, the oxidation is of course the same whether the oxy- 
hemoglobin carried to them by the blood was formed in a pure atmosphere 
of oxygen or in air, of which it comprises only about 20 per cent. The 
slight increase in the oxyhaemoglobin of the blood has no appreciable effect, 
as more oxygen is offered to the tissues normally than they can assimilate. 
It is therefore inconceivable that the very slight increase in the quantity of 
oxygen in the blood can have any effect on the oxidation in the tissues, but 
if the gas be inhaled under high pressure, the augmented tension in the 
blood may induce some symptoms, and this is according to Smith the ex- 
planation of a tendency to tetanic convulsions which he found developed in 
animals under these circumstances ; hilarity and some other nervous effects 
are said to have been induced in man in some instances, and these may also 
be interpreted as the results of the high oxygen tension in the blood, if they 
were not the products of fancy and suggestion. The apnoea which is ob- 
served in animals after vigorous artificial respiration is due not to an excess 
of oxygen in the blood, but to the diminished amount of carbonic acid prob- 
ably, for the oxygen of the blood in apnoea is practically the same in amount 
as that during ordinary respiration. Oxygen inhalation is therefore incapa- 
ble of increasing the oxidation in the tissues, or in fact of modifying in any 
way the metabolism, and experience has shown it to be valueless in such 
constitutional diseases as diabetes and gout, in which, moreover, it has been 
demonstrated that there is no deficiency in the oxygen of the blood. 

The further question arises whether oxygen inhalation is likely to be of 
benefit in the cyanosis due to severe cardiac or pulmonary disease. Improve- 
ment is very often observed clinically, the skin losing its dark color, and the 
respiration and heart becoming less rapid and labored as soon as the inhala- 
tion is commenced, and alarming symptoms returning when it is stopped. 
This may be explained by the larger amount of oxygen dissolved in the 
plasma ; when air is breathed, the plasma contains only about 0.6 per cent, 
of oxygen in simple solution, but when oxygen is inhaled the percentage 
may rise to 3 per cent, and this may reinforce the oxygen carried by the 
haemoglobin. In cases in which only a small quantity of blood is passed 
through the lungs owing to circulatory disorder or where the aerating surface 
of the lungs is diminished by exudation, this small supplementary supply of 
oxygen may be of importance. Again the air actually inspired does not pass 
directly i a to the alveoli, but diffuses from the wider air passages into the 
narrower ones and then reaches the absorbent surfaces. Pure oxygen diffuses 
more rapidly and in larger quantity into the alveoli than when it is mixed 
with nitrogen, and it is therefore conceivable that when the movement of 
the air in the air passages is insufficient, oxygen may give relief by diffusing 
in larger quantity into the alveoli. Insufficient movement of the air currents 
may be due to obstruction of the respiratory tract, as in asthma or severe 
bronchitis, or to slow and shallow breathing from depression of the centre. 
Accordingly, the inhalation of oxygen is said to be followed by relief in 
some cases of asthma and bronchitis, and it has been recommended in nar- 
cotic poisoning. 

When the haemoglobin of the blood is so altered as to be incapable of 
transporting oxygen to the tissues, as in cases of poisoning with carbon mon- 
oxide, nitrites, chlorates, nitrobenzol, etc., oxygen inhalation is indicated, for 
it has been shown by Haldane and others that the plasma dissolves enough 
oxygen to maintain life when that supplied by the blood corpuscles is insuf- 
ficient. The inhalation has to be continued until the symptoms of deficient 
aeration have disappeared. 



590 INORGANIC SALTS, ACIDS AND BASES. 

Many microbes are killed or at any rate much retarded in their growth 
when freely exposed to the air, and attempts have been made to treat pul- 
monary phthisis by oxygen inhalation. The results have been less disas- 
trous than those of some of the other treatments by inhalation, but no dis- 
tinct benefit has accrued, and in some cases haemoptysis has been induced 
by it from some unexplained cause. Smith has recently found that the in- 
halation of oxygen under some pressure causes irritation, congestion and 
consolidation of the lungs in mice and birds. 

Oxygen is inhaled through a mask connected with a large container which 
is filled from a tank of the compressed gas. Very often the oxygen may be 
diluted with air and for this purpose a small opening may be made in the 
mask. 

Ozone, or active oxygen (0 3 ), is a much more powerful oxidizing body than 
ordinary oxygen, but is more easily reduced than peroxide of hydrogen. 
It has a curious phosphorous odor and is somewhat irritant to the respiratory 
membranes, but it is almost always accompanied by nitrogen oxides, and 
some of the properties which have been ascribed to ozone may be due to 
these impurities. It is rapidly decomposed by living matter, and it seems 
very improbable that it can be absorbed into the blood ; yet Binz and 
Schulz believe that ozone induces narcosis in dogs, rabbits and kittens, and 
Schulz found in experiments in which ozone was inhaled repeatedly for long 
periods that it induced vomiting and dyspnoea, bronchitis, oedema and blood- 
extravasation in the lungs ; conjunctivitis also occurred in some experiments. 
Schulz ascribes these symptoms to the ozone, but they may be due in part at 
any rate to the impurities, or perhaps to oxygen. 

Ozone has undoubtedly antiseptic properties, but these are only apparent 
when air contains 13.5 mg. or more per litre, a concentration which it is 
quite impossible to attain in practice. Even this disinfects only the air itself 
and the surfaces of objects, as the ozone loses its oxidizing properties when- 
ever it comes in contact with organic matter and therefore fails to penetrate. 

Ozone inhalation has been recommended in the hope of increasing the 
oxidation of the tissues, and as an antiseptic in pulmonary phthisis, but its 
irritant properties preclude its use here, and it has been generally discarded. 
It was supposed to be formed in turpentine oil on standing, and old turpen- 
tine oil was therefore recommended in cases of phosphorus poisoning, 
with the hope that it would tend to oxidize the phosphorus and render it 
harmless. Recent investigations show, however, that no ozone is formed in 
turpentine oil, and there is no reason to suppose that the treatment is of 
benefit. 

Antozon is a mixture of oxygen and peroxide of hydrogen, and many other 
so-called solutions of ozone contain only small percentages of the peroxide 
and no ozone proper, as, though the latter is soluble in water, it decomposes 
very rapidly, only traces of it being found in the solution after 10-15 days. 
It breaks up into oxygen, and does not form hydrogen peroxide. 

The ozone of the air has been appealed to, in order to explain and adver- 
tise the benefits induced by many watering places and forest resorts but it 
has never been satisfactorily proved that the air in these localities contains 
more ozone than in other less favored places. The curative agency is gen- 
erally the change of scene and interests, and the dietary. 

Bibliography. 

Smith. Jonr. of Physiol., xxii., p. 307; xxiv., p. 19. 

Jlaldane, Makgill and Mavrogordato. Jour, of Physiol., xxi., p. 160. 

Michael is. Verhandl d. Congresses f. inn. Med., 1900, p. 503. 

Binz. Berl. klin. Woch., 1882 and 1884. 

Sonritag. Ztschr. f. Hygiene, viii., p. 95. 

Cash. Reports of Brit. Local Gov. Board, 1885. 

Schulz. Arch. f. exp. Path. u. Pharm., xxix., p. 364. 

Pallop. Inaug. Diss., Dorpat. 1889. 



PEROXIDE OF HYDROGEN, 591 

XXVII. PEROXIDE OF HYDROGEN. 

Hydrogen peroxide or dioxide (H 2 2 ) tends to break down into 
water and oxygen very rapidly in the presence of many substances, 
which in themselves may be either oxidizing or reducing. Among the 
bodies which induce this decomposition or catalysis are all forms of 
living matter, and the peroxide of hydrogen is therefore decomposed 
when brought in contact with the tissues, the oxygen thus liberated 
in a nascent condition tending to oxidize its surroundings ; the chief 
effects of this liquid are therefore due to its oxidizing properties. It is 
generally met with in dilute solution in water, and in this form alone 
is used in medicine. Brought in contact with the skin, peroxide of 
hydrogen solution is decomposed, and numerous bubbles of oxygen are 
formed, 1 but this decomposition proceeds much more rapidly when it is 
applied to denuded surfaces or to mucous membranes. The oxygen is 
formed in such quantity that some irritation may follow, and thus 
dogs often vomit when it is administered in quantity by the mouth. 
When it is injected subcutaneously, a large amount of oxygen is 
formed in the subcutaneous tissues, but some of the peroxide escapes 
decomposition and is absorbed into the blood. Here the decomposi- 
tion proceeds more violently, the red blood cells having a strong cata- 
lytic action, and the oxygen set free may cause emboli and lead to 
sudden death. The formation of emboli is seen most frequently in 
the rabbit, but was in all probability the cause of death in one case of 
fatal poisoning in man, in which a solution of hydrogen peroxide had 
been used to wash out the pleural cavity. 2 Emboli are not formed in 
the dog on hypodermic injection, nor in either dogs or rabbits poisoned 
by the stomach — in the latter case probably because the liquid is more 
slowly absorbed and is almost entirely decomposed in the mucous 
membrane. Even in the blood and tissues the whole of the peroxide 
is not decomposed, for several observers have found traces of it ex- 
creted in the urine. 

Injected intravenously in either dogs or rabbits the peroxide is rap- 
idly decomposed in the blood, and forms emboli which prove immedi- 
ately fatal by stopping the circulation through the lungs, heart and 
brain. 

The action of hydrogen peroxide, then, apart from its local effects is ex- 
plained by its obstructing the blood vessels mechanically. Colasanti has 
stated recently that in addition it forms methsemoglobin in dogs and thus 
leads to a marked decrease in the metabolism from the non-aeration of the 
tissues, but his statement requires farther confirmation. 

The catalytic decomposition of the peroxide is not necessarily asso- 
ciated with the life of the tissues, for it occurs also in excised organs 
and in drawn blood. In fact, it was formerly supposed that it took 
place only in the blood outside the tissues, and that the circulating 
blood had no effect on it, but this has been shown to be erroneous. 

1 A concentrated solution is said to corrode the skin, leaving a white eschar. 

2 In several other instances hemiplegia has been observed, apparently from embolism 
of the cerebral arteries. 



592 INORGANIC SALTS, ACIDS AND BASES. 

The different organs vary considerably in their catalytic power, the 
red blood cells and the liver cells being the most active, and it has 
been stated that this action of the tissue cells is closely associated with 
the presence of nucleoproteids (Gottstein, Spitzer) ; but Loew has 
shown that it is due to the presence of a widely distributed ferment 
(catalase) in most instances. 

The catalysis of hydrogen peroxide occurs in the lower forms of life 
as well as in the higher. Thus germinating seeds, yeasts, infusoria 
and the microbes all free oxygen from the solution, and in fact, a 
rough estimate of the number of microbes in water may be formed 
from the amount of oxygen given off by it on the addition of the per- 
oxide (Gottstein). This decomposition is fatal to most of these lower 
forms, presumably from the nascent oxygen, and peroxide of hydrogen 
is therefore a powerful antiseptic, a three per cent, solution proving 
as strongly bactericidal as a one per mille solution of corrosive subli- 
mate ; but when the microbes are contained in a medium with much 
organic substance, as in wounds, the bactericidal action is very much 
reduced. 

In recent years, attention has been drawn to other bodies analogous 
to hydrogen peroxide, some of which possess powerful microbicidal 
properties. The peroxide is represented by the structural formula 
H — O — O — H and one of the hydrogens may be replaced by benzoyl 
or acetyl, forming C 6 H 5 CO — O — OH (benzo-peracid) or CH 3 CO 
— OOH (aceto-peracid). These have been shown to be much more 
powerful germicides than hydrogen peroxide, while they give off 
oxygen less readily ; in fact they are comparable only to corrosive 
sublimate in their destructive effect on microorganisms and even sur- 
pass it in favorable conditions. This suggests that the disinfectant 
action of this group is not really due to its liberating oxygen only, 
otherwise the activity of these peracids would be less than that of the 
peroxide as they part with their oxygen less readily. It is possible, 
however, that the difference really arises from the way in which the 
oxygen is liberated ; for example, the peracids may penetrate the 
microbes and free oxygen in their interior, while the peroxide is re- 
duced before it passes through the cell-wall. The peracids are pre- 
pared with difficulty and are very unstable bodies, so that it is unlikely 
that they will prove of value in practical medicine. But they are 
formed when the aqueous solutions of some more readily available 
substances are allowed to stand for some time. In these both the hy- 
drogen atoms of hydrogen peroxide are replaced by organic radicles 
forming organic peroxides such as diacetyl peroxide (CH 3 CO — O — O 
— COCH3) and benzoyl-acetyl-peroxide (C 6 H,CO— O— 6— COCH 3 ). 
On dissolving these in water, the peracids are formed and the solutions 
are very powerful disinfectants which have been suggested for surgical 
use and also as intestinal disinfectants ; practical clinical experience 
alone can decide whether they possess that value which their results 
in the laboratory seem to indicate. 



PEROXIDE OF HYDROGEN. 593 

Preparation. 

Aqua Hydrogenii Dioxidi (U. S. P.), Liquor Eydrogenii Peroxidi (B. P.), 
solution of hydrogen dioxide or peroxide, contains about 3 per cent, by 
weight of the pure dioxide. Each volume of this solution is capable of set- 
ting free 9-11 volumes of oxygen when completely decomposed. Some acid 
is added to the peroxide solution in order to retard its decomposition, but it 
gradually changes when kept, so that only freshly prepared solutions are of 
full strength. The solution is colorless and odorless, but has an acid taste 
from the added acid, and the oxygen freed in the mouth gives a curious sen- 
sation and forms a froth. 

Therapeutic Uses. — Hydrogen dioxide is used locally as a disinfect- 
ant solution in suppuration, diphtheria and urethral infection. In pus 
cavities the oxygen is freed with great rapidity, and the pus-corpuscles 
are said to be disintegrated. The catalysis is due in part to these cor- 
puscles, in part to the microbes, and the extent of the suppuration 
may be estimated from the amount of effervescence. Peroxide solu- 
tions differ from most other disinfectants in the short duration of the 
action, which passes off as soon as all the oxygen is liberated. In ad- 
dition to its microbicidal action proper, this agent loosens and destroys 
masses of infected material by the mechanical effect of the liberation 
of the gas, and the wound or cavity is thus cleaned by it more per- 
fectly than by washing with ordinary antiseptic solutions. The solu- 
tion has been recommended for use in ophthalmic practice, and for 
this purpose may be diluted one half. 

Bibliography. 

Gutimann. Virchow's Arch., lxxiii., p. 23; lxxv., p. 255. 

Schwerin. Ibid., lxxiii., p. 37. 

Altehoefer. Centralbl. f. Bacterid., viii., 1890, p. 129. 

Pane. London Medical Becord, 1891. 

Colasanti and Brugnola. Arch. Ital. de Biol., xxv., p. 228. 

GotMein. Virchow's Arch., cxxxiii., p. 295. 

Spilzer. Pfluger's Arch., lxvii., p. 615. 

Honsell. Beitriige z. klein. Chir., xxvii., p. 127. 

Lozvo. U. S. Depart, of Agriculture Rep., No. 68. 

Novy and Freer. Journ. of Exp. Med., vi. (Peracids. ) 

Other Oxidizing Disinfectants. 

Other oxidizing bodies have been used as antiseptics and disinfect- 
ants. Thus Calcium Peroxide or Gorit has been recommended as a 
gastric and intestinal disinfectant for children in doses of 0.2—0.6 G. 
in milk ; the action may depend in part on the calcium hydrate formed 
as well as on the oxygen liberated. - 

Similarly the Persulphates of potassium and sodium (Na 2 S 2 O s ), per- 
sodine, possess strong oxidizing properties from their liberating oxygen 
in contact with organic matter. They are only feebly poisonous but 
have not been extensively used as yet. 

Some older and better known disinfectants also owe their powers to 
liberated oxygen, and among these that most largely employed is the 
Permanganate of Potassium. 

When a solution of this salt comes in contact with organic matter, 
such as albumin, the permanganate at once parts with some of its 
38 



594 INORGANIC SALTS, ACIDS AND BASKS. 

oxygen, which attaches itself to the albumin. Permanganate is thus 
poisonous to protoplasm, not through the presence of the whole mole- 
cule, but in consequence of the oxidation of the proteids. As soon as 
the permanganate is reduced, it of course loses this action, so that the 
oxidizing effect is limited to the skin and the surface of the mucous 
membranes. Concentrated solutions irritate, and even corrode the skin, 
and induce gastro-enteritis when swallowed. Permanganate solutions 
are antiseptics of considerable power, owing to their oxidizing and thus 
destroying bacteria. They fail to penetrate deeply in an active form, 
and this renders them of less value than many other antiseptics, except 
in very superficial infection. 

Preparations. 

Potassii Permanganas (U. S. P., B. P.) (KMn0 4 ) forms slender crystals of 
a dark purple color and a sweetish, afterwards disagreeable and astringent 
taste, soluble in sixteen parts of water, reduced by alcohol and other or- 
ganic bodies. 0.05-0.2 G. (1-3 grs.), in pills made up with kaolin. 

Liquor Potassii Permanganatis (B. P.), a 1 per cent, solution in water. 
2-4 fl. drs. 

Therapeutic Uses. — The permanganate has been used internally in 
amenorrhoea and chlorosis. 

Externally it is used for its disinfectant and deodorant action, as an 
application to gangrenous ulcers, cancerous sores, diphtheria, and gon- 
orrhoea. In dilute solution it may be used as a gargle and mouth 
wash (1 per cent.), to disinfect the hands (1—3 per cent.), which it stains 
brown, and for other similar purposes. 

It has recently been recommended in poisoning with phosphorus, 
prussic acid, morphine and other alkaloids, on the theory that these 
poisons are oxidized by it in the stomach, and thus rendered harm- 
less. For this purpose it is given in J per cent, solution. It may be 
questioned whether much permanganate reaches the stomach unreduced, 
and the method is certainly less reliable than the stomach tube. Only 
the poison actually in the stomach is destroyed, permanganate having, 
of course, no effect upon that absorbed into the blood. In snakebite, 
permanganate has been advised, and it undoubtedly has some action on 
the poison when it comes in contact with it, and may therefore be 
used to wash the wound and also to inject around it ; it has no effect 
upon the poison already absorbed. 

Condy ? s Fluid is a strong solution of impure permanganate, which 
is of use to disinfect and deodorize urinals and faeces, but must be 
poured on them, and cannot be employed to disinfect rooms. 

Some of the caustics owe part of their action to the oxygen liber- 
ated when they come in contact with organic matter. Thus Chromic 
Acid destroys tissue in part through its acidity but this is reinforced 
by its oxidizing powers. 

XXVIII. PHOSPHORUS. 

In the early part of last century phosphorus played a very important 
role in therapeutics, and, in fact, was regarded almost as a panacea, 
but at present its use is much more restricted, and some doubt is en- 



PHOSPHORUS. 595 

tertaiued as to its possessing any therapeutic value whatever. At 
the same time it has been the subject of much and laborious investiga- 
tion, partly because it has frequently given rise to poisoning, and partly 
because the study of its effects has thrown much light on some physi- 
ological and pathological processes. It differs from most poisons in 
acting for the most part on certain phases of the animal metabolism, 
and in having comparatively little direct action at the point of appli- 
cation, or, indeed, upon any single organ. 

Phosphorus is absorbed with difficulty, because it is very insoluble 
in water and the body fluids and is only slowly volatilized at ordinary 
body temperature. Large masses of phosphorus may thus pass through 
the alimentary canal without serious effects, because they fail to be 
dissolved and absorbed. But when it is taken in a finely divided con- 
dition or in solution in oil, it gives rise to symptoms in very small 
quantity, and has been found to induce fatal poisoning in man in doses 
of 0.05—0.1 G. (1—2 grs.). 1 In these conditions it is absorbed partly as 
vapor, partly in solution in water, which dissolves only traces how- 
ever, and probably chiefly in solution in the fats and oils, in which it 
is much more soluble. Phosphorus vapor is also absorbed by the lungs, 
and the symptoms of chronic poisoning in match factories are believed 
to arise in this way. It does not seem to be taken up from the skin, 
and has in fact little effect unless when rubbed on it, when it ignites 
and gives rise to severe burns ; phosphorus burns do not cause 
phosphorus poisoning, however, as is sometimes stated. The red 
amorphous phosphorus is much less poisonous than the ordinary yel- 
low form, because it is less soluble and also less volatile, and conse- 
quently fails to be absorbed. 

Phosphorus exists in the blood as such, and the effects on the tissues 
are unquestionably due to the element itself, and not to the oxygen or 
hydrogen compounds, as has been supposed. Some phosphuretted 
hydrogen (PH H ) may be formed in the bowel, but is comparatively 
unimportant, the great mass of the phosphorus being absorbed un- 
changed. As soon as it is oxidized, phosphorus loses its specific ac- 
tion, all of the acids being comparatively harmless. Phosphorus has 
been detected in the blood, and, it is said, in some of the excretions. 

It is devoid of action on albumins in solution, and has no immediate 
irritant effects, such as are seen in poisoning with the heavy metals. 

Symptoms. — When a poisonous dose of phosphorus is swallowed, no 
effects are elicited as a general rule for several hours. The first symp- 
toms are pain and discomfort in the region of the stomach, nausea and 
eructation of the vapor with its characteristic garlic odor, and then 
vomiting, the contents of the stomach having the same odor, and being 
phosphorescent in the dark. Later, bile may be vomited, and some 
diarrhoea may set in, although this is not a common symptom. The 
nausea and vomiting often continue without further symptoms for 

1 Phosphorus is often used in suicide, generally in the form of rat poison or of match 
heads. Each phosphorus match is estimated to carry 8-5 mg. of phosphorus, so that 
15-20 match heads are sufficient to induce fatal poisoning. 



596 INORGANIC SALTS, ACIDS AND BASKS. 

several days, but frequently disappear, and the patient apparently 
recovers, particularly if the dose has been small, or if most of it has 
been removed by vomiting or by washing out the stomach. In the 
course of a few days, however, the symptoms recur, and are generally 
accompanied by some jaundice ; the pain extends from the stomach to 
the liver, and soon to the whole of the abdomen. The vomited matter 
no longer contains phosphorus, but may be bloody. The patient com- 
plains of general weakness and faintness ; the pulse is weak, the liver ex- 
tends far below the ribs, and the urine shows characteristic changes (see 
page 602); haemorrhages occur from the nose, bowel, uterus, and under 
the skin, and eventually a condition of collapse and fatal coma follow. 
Convulsions and delirium have been observed in a considerable pro- 
portion of cases towards the termination of the intoxication. Death 
may occur, however, in the first stage or early in the second, before 
complete exhaustion is reached, and in these cases would seem to be 
best explained by the direct action of the poison on the heart. If only 
a small quantity be swallowed or if active therapeutic measures be 
taken early, the patient may recover without any secondary symptoms, 
and even when these have followed, the prognosis is not hopeless, for 
the symptoms slowly disappear in a certain proportion of cases. 

Exposure to the fumes of phosphorus has long been known to give 
rise to periostitis and necrosis of the lower jaw. The disease begins 
from a carious tooth or from some lesion of the gum, and may involve 
most of the jaw, which becomes swollen and painful and eventually 
evacuates large quantities of pus with pieces of dead bone. This ne- 
crosis was formerly frequent in match factories, but has become rarer 
since amorphous phosphorus has been substituted for the yellow form, 
and since greater attention has been paid to the ventilation of the fac- 
tories and to the condition of the teeth of the employees. Magitot has 
recently advanced the opinion that exposure to phosphorus fumes 
gives rise to a mild chronic form of poisoning, quite aside from the 
necrosis, which is comparatively rare. The symptoms are cachexia, 
slight jaundice, anaemia, and abuminuria, and in more advanced cases 
chronic enteritis and diarrhoea, bronchitis, and a curious fragility of the 
bones. 

Action : Fatty Degeneration. — A very striking feature in phosphorus 
poisoning, and one that was early recognized in its history, is the ap- 
pearance of numerous fat globules in the cells of many organs, notably 
in those of the liver, kidney, gastric and intestinal glands, and in the 
muscle fibres of the heart, stomach, intestine, smaller arteries and often 
of the skeletal muscles. The question has been raised whether this fat 
is formed by the degeneration of the protoplasm of the cells in which 
it is found, or whether it is not transported from other parts of the 
body and only deposited in these cells, the school of Voit maintaining 
the former view, while Pfliiger and his pupils uphold the latter. The 
advantage at present seems to lie with Pfliiger, who has shown that 
the total fat of the body is not increased by phosphorus, although this 
has been met by Lindemann's explanation that a certain amount of fat 



PHOSPHOR US. 59 7 

is destroyed during the intoxication, and that if more fat were not 
formed from the proteids through the action of the poison, there- would 
be found a marked deficiency at death. A strong argument for 
Pfluger's view is adduced by Rosenberg, who found that when an 
animal has been fed on foreign fats (e. g., a dog upon mutton suet) and 
is then poisoned with phosphorus, the fat found in the liver cells is 
that characteristic of the food and not that of the poisoned animal as 
might be expected if it were derived from the proteids. The question 
cannot yet be said to be determined, although the burden of proof 
certainly seems to rest on the defenders of the earlier view that the fat 
arose from the degenerated proteids of the cells in which it is found. 
The fatty degeneration or infiltration sets in only after some time, and, 
in fact, accompanies the secondary symptoms for the most part, although 
the cells of the stomach and upper part of the intestine suffer sooner, 
and the beginning of this process is probably the cause of the early 
vomiting. 

In phosphorus poisoning, as in other instances of fatty degeneration, 
the process commences in cloudy swelling of the cells followed by the 
appearance of granules, which soon develop into fat globules. Even- 
tually the degenerated cells break up into detritus. 

Another feature in phosphorus poisoning, which is, however, better 
seen after repeated small doses than after a single large one, is the 
Proliferation of the Interstitial Connective Tissue of the stomach, liver 
and kidney, which finally induces typical cirrhosis of these organs. It 
was formerly supposed that this indicated a specific irritant action of 
the phosphorus vapor on the connective tissue, but many pathologists 
now regard this proliferation as a secondary result of the necrosis of 
the parenchyma cells. In animals poisoned by the prolonged adminis- 
tration of small quantities of phosphorus, the ordinary effects of hepatic 
and renal cirrhosis have been induced, such as dropsy, anaemia and 
cachexia. 

Besides the cells which have undergone fatty degeneration, the liver 
often contains numerous microscopic areas of necrotic tissue and in 
other parts actively dividing parenchymatous cells. 

When very minute quantities of phosphorus are administered to 
animals, no poisoning results, but according to Wegner a specific 
action on the Bones is induced, especially in young animals, in which 
the bones are still growing. Thus, in young rabbits, quantities of 
Iq-^ mg. given for several weeks are found to be followed by char- 
acteristic changes in the growth of the long bones, apparently in- 
duced by the phosphorus acting as an irritant or stimulant to the 
bone-forming cells (osteoblasts). Wherever cancellous bone is being 
formed from cartilage, phosphorus is stated by Wegner to cause the 
deposit of a layer which resembles the dense bone of the shaft in 
the normal animal in general appearance and also histologically. 
This layer of dense bone at the growing point is at first the only 
change induced, but if the treatment lasts longer, the soft cancellous 
bone which was deposited before the phosphorus treatment began, 



598 INORGANIC SALTS, ACIDS AND BASES. 

is gradually absorbed. The medullary cavity of the bone is thus 
enlarged, and may, in fact, extend into the epiphyses, which in the 
normal bone are tilled with cancellous tissue, but which now form part 
of the much lengthened cavity. Eventually the whole of the cancel- 
lous bone may be absorbed, and a similar process of absorption begins 
in the bone formed at first under phosphorus, while the dense deposit 
is pushed further into the remaining cartilage. The development of 
bone from cartilage is not the only process affected, however, for 
Wegner states that in the bone deposited from the periosteum a some- 
what similar change is induced, as is shown by its becoming denser 
and by the Haversian canals being much contracted in size. In full- 

Fig. 50. 





A B 

Section of the head of the femur in calf. A, normal, B, after treatment with minute doses of 
phosphorus. C, the cap of dense bone at the growing point. (After Wegner. ) 

grown animals the changes in the bone are much less distinct, but the 
lamellae of the spongy tissue are said to be thickened by phosphorus 
treatment, and in the fowl Wegner states that the medullary cavity may 
be completely obliterated by the deposition of hard bone. Wegner 
supposes that this effect on bone is due to a specific action on the bone- 
forming cells, analogous to that which he observed in the connective 
tissue of the liver. As has been mentioned already, however, the cir- 
rhosis of the liver in chronic phosphorus poisoning is believed by many 
not to be due to primary irritation of the interstitial tissue, but to be 
secondary to the destruction of the parenchymatous cells, so that this 
analogy is rendered doubtful. 

Wegner found further that when the calcium salts were withdrawn 
from the food of animals treated with phosphorus, the exaggerated ac- 
tivity of the bone-forming cells continued, but no lime was deposited, 
so that the bone presented the appearance of rickets. The same re- 
sult has, however, been obtained by other investigators by the with- 
drawal of calcium without phosphorus. Kassowitz took up the inves- 



PHOSPHORUS. 599 

tigation some twelve years later, and observed the layer of white dense 
bone described by Wegner at the edge of the ossifying cartilage, but 
regards it not as the result of excessive activity of the osteoblasts, but 
as due to a slower absorption of the calcified cartilage from a less rapid 
extension of the blood vessels than is normal. With large doses he 
produced appearances closely resembling those of rickets. Several 
other investigators have observed changes in the bones after phos- 
phorus, so that there is good reason to believe that it possesses some 
specific action on them, although some writers failed to obtain definite 
results and of those who observed a modification in the growth no two 
agree in the description of the changes or in their interpretation. This 
specific action on the bone-forming tissues and particularly on the 
periosteum has been used by Wegner to explain the necrosis of the 
jaw in match factories. He supposes that the phosphorus vapor reach- 
ing the periosteum of the jaw through a carious tooth or some lesion 
of the gums, excites a mild periostitis, which in turn leads to the for- 
mation of new layers of bone around the jaw. Necrosis of the bones 
has not been satisfactorily demonstrated in animals exposed to phos- 
phorus vapor, although numerous experiments have been performed 
with the object of studying its development. The view of the latest 
investigators is that microbial infection is necessary to permit of the 
changes observed clinically, but that phosphorus induces some change 
in the bones which predisposes them to infection by the tubercle ba- 
cillus and other organisms which induce necrosis. The occurrence of 
necrosis of the jaw is in fact a strong argument for the correctness of 
the view that a specific action on bone exists, for under no other poison, 
even when much more irritant vapor is inhaled, does a similar process 
occur in man. The exact nature of this action on bone, and its rela- 
tion to rickets and to osteomalacia must, however, be left for further 
research to determine. 

Phosphorus weakens and slows the Heart when it is applied to it 
directly in the frog, or by intravenous injection in mammals. In 
many cases of acute poisoning in man, however, the heart does not 
seem to be seriously affected until very late, and this is particularly the 
case when comparatively small quantities have been absorbed. In 
those cases in which large amounts are swallowed in solution or in fine 
division, and in which death occurs before any secondary symp- 
toms have been developed, the fatal issue is generally ascribed to the 
cardiac action. This direct action on the heart must be distinguished 
from the fatty degeneration of the cardiac muscle, which is seen in the 
later stages of poisoning, for no degeneration of the heart, and, in fact, 
no pathological changes whatever, may be found in those rapidly fatal 
cases. Phosphorus acts on the heart muscle directly, and does not 
seem to affect the regulating nerves in any way. According to Pal, 
the blood-pressure is lowered in some cases not by cardiac action, but 
by the dilation of the vessels. 

The Blood is but little changed outside the body by phosphorus, 
for though Araki states that the haemoglobin parts with oxygen more 



600 INORGANIC SALTS, ACIDS AND BASES. 

slowly than usual, the difference is trifling. In many cases of fatal 
poisoning, the blood is found not to clot so readily as usual, and some- 
times to remain fluid for forty-eight hours or more. According to 
Corin and Ansiaux and Jacobj this occurs only in cases in which the 
patients live for several days, and is not a direct effect of the poison, 
but is due to the changes in the intestine and liver, which lessen or 
entirely destroy the fibrinogen. Jacobj states that the blood not only 
fails to clot but is capable of redissolving fibrin and attributes this to 
the presence of the autolytic ferment of the liver. 

The absence of clotting in the blood may be a factor in the haemor- 
rhages which are met with among the symptoms of the second stage, 
but the immediate cause of these is the fatty degeneration of the mus- 
cular coat of the smaller arteries throughout the body. These changes 
in the blood vessels may perhaps explain the oedema of the retina, 
which is seen in animals poisoned with phosphorus, though these have 
also been attributed to some change in the blood. Occasionally gan- 
grene of the extremities has been observed in phosphorus poisoning, 
probably owing to the changes in the vessel walls. 

Small doses of phosphorus generally increase the number of the red- 
blood cells in man, and even in poisoning a sudden or gradual increase 
in these may occur, along with a diminution of the leucocytes. The 
haemoglobin is not correspondingly augmented, however. In the lower 
animals the effect on the blood cells varies a good deal ; in the dog, a 
considerably increased destruction is generally believed to take place ; 
in the rabbit, no distinct alteration in the number of the red cells but 
some leucocytosis has been observed, while in fowls an increase in the 
leucocytes accompanies a marked destruction of the red cells ; in the 
frog the number of red cells is not reduced. 

The peripheral Nerves and Muscles do not seem to be affected in 
phosphorus poisoning, except in so far as the latter undergo fatty de- 
generation. An excised muscle lives almost as long in salt solution 
containing phosphorus as in the unpoisoned solution. 

The Central Nervous System is also little changed by phosphorus. 
The coma and convulsions which appear before death may be due 
rather to the disordered metabolism than to any direct influence, as is 
shown by the fact that consciousness is preserved throughout the first 
stage, and as a general rule until late in the second. Certain changes 
in the nerve cells, which were alleged to be induced by the action of 
phosphorus, have been shown to be due to the method of hardening 
the tissues that was used. 

The fatty degeneration of the epithelial cells of the Stomach and 
Intestine explains the abdominal pain, the vomiting and the occasional 
diarrhoea seen among the secondary symptoms. The earlier phases of 
this action may be the cause of the vomiting and nausea of the first 
stage. This degeneration occurs also when phosphorus is injected 
hypodermically, and is therefore of the same nature as that in the 
other organs. The cells of the stomach first attacked are those of the 
glands, and the condition has been termed gastradenitis. 



PHOSPHORUS. 601 

The fatty changes in the Liver cause a considerable increase in the 
area of hepatic dulness, and at the same time induce some pain and 
tenderness over the organ. 

The icterus of phosphorus poisoning has been examined by Stadel- 
mann in dogs. He found that the changes in the bile secretion may be 
divided into three phases, in the first of which a larger amount of bile 
pigment is excreted than usual, this denoting an unwonted activity of 
the liver cells. In the second phase the bile becomes clouded, is less 
deeply colored and more viscous, and icterus makes its appearance 
in the skin and conjunctiva. The secretion in this stage seems to be 
derived largely from the mucous cells of the smaller bile ducts, and 
contains comparatively little of the excretion of the liver cell proper. 
In the third phase, which is that of recovery, the bile loses its turbidity 
and viscosity, and is very dark in color, because the pigment which 
was deposited in the tissues during the second stage is reabsorbed and 
excreted in the bile ; the jaundice color of course disappears from the 
skin as the bile pigment is reabsorbed. The bile salts are also very 
much reduced in phosphorus poisoning. Stadelmann attributes these 
changes to the bile capillaries being rendered less pervious, by the en- 
larged liver cells or the proliferating connective tissue pressing on them 
and narrowing their lumen. This prevents the bile which is formed 
by the liver cell from reaching the gall bladder, and the pigment is 
therefore absorbed and gives rise to jaundice. The pale viscous fluid 
which escapes from the ducts in the second stage is probably not true 
liver secretion, but mucus from the ducts. During recovery, the hepatic 
cells lessen in size, the pressure on the bile capillaries is relieved and 
the secretion escapes, while the pigment which was distributed through 
the tissues is reabsorbed and excreted by the ordinary channel. The 
jaundice may also be accounted for in part by the destruction of the 
red ceils of the blood and consequent increase of pigment formation in 
the liver. This view is supported by the fact that in the rabbit, in which 
the red cells are not decomposed by phosphorus, no icterus is observed, 
whiLe in the dog, in which some of the cells are destroyed, it is very 
marked. In man, however, there is no evidence that the red cells are di- 
minished in number, yet jaundice is one of the commonest symptoms. 

In addition to the fatty infiltration of the cells and the changes in 
the bile, the liver has been shown to undergo a specific alteration in its 
activity, which is manifested by the presence of unusually large quanti- 
ties of ammonia and of leucin and ty rosin, which are not among its 
normal constituents. When the liver of an unpoisoned animal is kept 
from putrefaction for some time, the tissue is broken down by the ac- 
tion of an autolytic ferment, and ammonia, leucin and tyrosin are 
formed in large quantity ; the liver in phosphorus poisoning under- 
goes the same changes when preserved from putrefaction, but the 
autolysis progresses much more rapidly. Jacob] therefore infers that 
phosphorus augments the activity of the autolytic ferment of the liver 
and thus leads to the presence in the living organ of some products 
which are absent in the normal one. He regards the disappearance of 



602 INORGANIC SALTS, ACIDS AND BASES. 

the fibrinogen of the blood as a further effect of this liver autolysis, for 
he found that the injection of the autolytic ferment into normal animals 
prevented coagulation. 

The fatty degeneration of the Renal Epithelium may account in part 
for the albuminuria, which is not generally severe, and is not infre- 
quently absent in cases of poisoning. Fatty casts and even globules 
of fat are often found in the urine in cases which run a chronic course. 
Blood and haemoglobin may also appear in it from haemorrhages into 
the kidney. The other changes in the urine are not referable to the 
renal disease, but to the modification of the general metabolism of the 
tissues, the kidneys merely excreting the abnormal products of decom- 
position which appear in the blood. 

These abnormalities in the Urine have been examined very often, 
but some discrepancies are still to be found in the accounts of different 
authors. The urine itself is often somewhat increased in quantity in 
the early stages of the intoxication, but afterwards becomes deficient, 
and towards death complete anuria may be observed. The increased 
urine is probably due to the increase of the urinary substances in the 
blood, while the diminution, which may occur early, may be explained 
by the small quantity of water absorbed from the stomach and intes- 
tine, by the degeneration of the secretory cells, or by the failure of the 
circulation. 

The nitrogen of the urine varies considerably in different cases. 
Very often in the first few days after the ingestion of the poison, it is 
markedly diminished in amount, but this is not due to any specific 
action of the poison, but to the prolonged nausea and vomiting which 
prevent the absorption of food ; the nitrogenous excretion thus cor- 
responds to that during the first few days of starvation. After this, 
however, a very considerable increase in the nitrogen is observed, even 
although the patient continues to fast, In the course of starvation a 
rise in the nitrogen excretion also occurs after some time, but this is 
never so great as that seen in phosphorus poisoning, so that the poison 
has generally been credited with a specific action increasing the waste 
of the nitrogenous tissues. The excretion of urea does not increase in 
proportion with the total nitrogen, in fact less urea is often excreted 
than in the first days of the intoxication. But the nitrogen excreted in 
the form of ammonia is much increased in man and the dog, while it 
is not altered in the rabbit. This excretion of ammonia suggests the 
formation of excess of acid in the tissues, 1 and as a matter of fact sar- 
colactic acid is found in very considerable quantity in the urine in man, 
the dog and the rabbit in phosphorus poisoning. The increased am- 
monia of the urine is therefore to be referred, at any rate in part, to the 
formation of this acid in the tissues, and if fixed alkalies are adminis- 
tered, the ammonia of the urine falls at once in amount because the 
alkali neutralizes the sarcolactic acid. 

The uric acid excreted is often somewhat increased in amount, but 
on the whole is little altered by phosphorus in man. This perhaps 
1 See Ammonia, Acids, pp. 502, 561. 



PHOSPHOR US. 603 

indicates that the nuclei of the cells are less subject to the action of 
the poison than the cytoplasm, and this is supported by histological 
examination, for the fat globules are found in the cell body, aud not 
in the nucleus. 

The other nitrogenous constituents of the urine are not so much 
affected, at any rate in man ; some increase in the extractive substances 
is observed, this forming but a small part of the nitrogenous increase 
however. Some abnormal products are occasionally, but by no means 
constantly seen. The best known of these are tyrosin and leucin crystals 
which are not always present in the urine, however, although they 
have been found in the blood in some quantity. Baumann found an 
increase in the substances of the aromatic series in the urine. Albu- 
min may be present in small amount, and peptone is sometimes ex- 
creted. In addition, Harnack describes some products which are not 
peptones but which are apparently closely related to the proteids. 

The chlorides of the urine are much reduced in amount, owing to 
the patient taking little or no food. The phosphates of the urine are 
often very considerably augmented, but not because of the excretion 
of phosphorus as phosphates, for the quantity absorbed is too small to 
cause any appreciable change. The increase in the phosphates is 
rather to be ascribed to an augmented waste of the tissues, and the 
sulphates are also excreted in larger quantity for the same reason. 

When icterus is present, the urine may be dark in color from the 
bile pigment excreted and bile acids are also often contained in it. 
Sarco lactic acid appears in considerable quantity, and is sometimes ac- 
companied by some sugar. 

The alterations in the urine point to some grave derangement in the 
Metabolism, by which, among other results, an excess of sarcolactic acid 
is formed in the tissues and is not oxidized to carbonic acid and water 
as in the normal organism. This acid has been found excreted into 
the stomach along with hydrochloric acid, and in the blood in the form 
of salts. Meyer found a considerable reduction in the alkalinity of the 
blood in phosphorus poisoning, the normal alkalies having been neutral- 
ized by this acid, and it seems probable that many of the symptoms 
of phosphorus poisoning may be due to the lessened alkalinity. The 
lactic acid is formed from glycogen, which has been found to be 
remarkably reduced in the liver in cases of phosphorus poisoning. 
Another body which disappears from the liver almost wholly is leci- 
thin, but this is probably due to the inanition. The appearance of 
lactic acid, sugar, and albumin in the urine is attributed by Araki to 
insufficient oxidation in the tissues, and in the statement that lack of 
oxidation plays a part in phosphorus poisoning, he only confirms the 
impression of many earlier writers. 

It is frequently stated that the decomposition of the proteids is ac- 
celerated, but this belief arises from the large amount of nitrogen in the 
urine, and this has been shown to be due for the most part to the for- 
mation of sarcolactic acid in excess, that is, to the retarded oxidation. 
A further complication of the question arises from the fact that deti- 



604 INORGANIC SALTS, ACIDS AND BASES. 

cient combustion in itself seems to increase the nitrogen of the urine, 
and it therefore seems possible to explain most of the deviations from 
the normal in the urine as the result of the lessened oxidation. At the 
same time it is quite possible that the proteid waste may be increased 
by phosphorus acting on the tissues in some other unknown way, as 
well as by diminishing their combustion. 

The frequent occurrences in the urine of leucin and tyrosin is ex- 
plained by the destructive changes in the liver cells, and in fact it is 
possible that this alteration of the liver is responsible for the symp- 
toms of insufficient oxidation, and that the specific action of phospho- 
rus is exercised on the liver, the other tissues being changed to a less 
degree or only indirectly. 

It was formerly believed that the fatty degeneration was dependent 
on lessened oxidation ; that the fat formed by the decomposition of the 
proteids could not be oxidized as it is normally, and therefore remained 
in the cell. But this is not consistent with the view prevailing at 
present, that the accumulation of fat in the liver and other organs is 
due to its migration from other parts of the body, so that the relation 
between the two phenomena is not so simple as has been supposed. 
Lessened oxidation and fatty degeneration occur together under so many 
conditions, however, that there must almost certainly be a causal re- 
lation between them, though it is impossible to state at present its 
exact nature. 1 

In view of the curious effect of phosphorus on the tissue change of 
the vertebrates, its action upon simpler forms possesses some interest. 
It has been found, however, that yeast, infusoria and bacteria are very 
little affected by the presence of this poison, and living microbes are 
found in large numbers on solid pieces of phosphorus. The ferments 
are also unaffected for the most part, pepsin and pancreatin acting in 
the presence of phosphorus. Curiously enough, although the oxida- 
tion is imperfect in animals poisoned with phosphorus, Hauser has 
found that if phosphorus be added to the blood which is perfused 
through an excised organ, the oxidation is as rapid as if no poison had 
been added. He found, however, that some of the synthetic processes 
of the body were probably retarded by it, for less hippuric acid was 
formed in a kidney perfused with blood containing phosphorus than in 
one in which normal blood was used. On the other hand the autolytic 
activity of the liver is augmented, as has been noted already. 

The Temperature is often low in the later stages of phosphorus 
poisoning, but slight fever is also observed in some cases. 

The Fate of phosphorus in the body is still obscure. It is possible 
that some of it is oxidized to phosphoric acid, and some phosphorus is 
said to be excreted by the lungs, although the statement that the breath 
becomes phosphorescent seems to be extremely improbable. It is also 

1 The lessened oxidation in the tissues was at one time believed to be due to the 
phosphorus using up the oxygen for its own oxidation, but this is obviously incorrect, 
for the amount of oxygen required for this would be quite insignificant, Another 
theory, that phosphorus acts by liberating nascent oxygen in the cells, is based on no 
sufficient evidence. 



PHOSPHOR US. 605 

excreted in the urine in some organic combinations, of which nothing 
is known, though they are said to be volatile. In pregnant animals 
poisoned with phosphorus, the foetus is found to undergo fatty degen- 
eration, so that the poison would seem to pass through the placenta. 

Phosphuretted hydrogen (PH 3 ) induces the same symptoms as phos- 
phorus, but is more rapidly fatal. The oxygen compounds do not 
seem to have any such effects, and for the most part are harmless ex- 
cept in very large doses. 

Preparations. 

Phosphorus (U. S. P., B. P.), a translucent, nearly colorless solid resembling 
wax in lustre and consistency. It emits white fumes in the air, which are 
luminous in the dark, and takes fire spontaneously. The fumes have the 
odor of garlic, and in dilute solution phosphorus has a harsh, disagreeable 
taste. It is very little soluble in water, more so in alcohol, and dissolves to 
about two per cent, in fats and oils. %-l rag. {iwr~h g r -) (B- P- ifar~$6 g r -)- 

Zinci Phosphidum (U. S. P.) (Zn 3 P 2 ), a gritty powder of a dark gray color, 
or crystalline fragments of a dark metallic lustre, and w r ith a faint odor and 
taste of phosphorus, insoluble in water or alcohol. 0.003-0.005 G. (aVrV gr.) 
in pill. 

Oleum Phosphorahim (U. S. P., B. P.) is a one per cent, solution in almond 
oil and ether. 0.05-0.1 c c. (1-2 mins.) (1-5 mins. B. P.). Phosphorated 
oil ought to be freshly prepared and kept in tightly stoppered bottles ; solu- 
tions of one per cent, tend to lose their strength by evaporation of the 
phosphorus and by oxidation, when the bottle contains air. It is said to 
keep better in more dilute solution (one per mille). It is probable that much 
of the oil dispensed is much under one per cent, in strength. 

Pilulx Phosphori (U. S. P.), each pill contains 0.6 mg. of phosphorus 

(rib gr.)- 

Pilula Phosphori (B. P.), 2 per cent., 1-2 grs. 

Spiritus Phosphori (U. S. P.) (Tincture of Phosphorus) is an alcoholic solu- 
tion containing 1.2 parts of phosphorus in 1,000 of alcohol. 0.3-1 c.c. 
(5-15 mins.). 

Elixir Phosphori (U. S. P.) contains about \ of the amount of phosphorus- 
of the spirits of phosphorus. 1-4 c.c. (15-60 mins.). 

Therapeutic Uses. — Phosphorus has been recommended in various 
diseases of the central nervous system and in neuralgia, but it is still 
questionable whether it is of any real benefit in these. There is more 
reason to believe in its virtues in bone disease, more especially in 
rachitis and osteomalacia, for in a number of instances marked im- 
provement has been observed in these diseases under its use. It is 
generally given in solution in cod-liver oil, and the benefit may be due 
in part to the menstruum, but not entirely, for Sternberg observed a 
relapse in a case of osteomalacia when pure cod-liver oil was substi- 
tuted for the phosphorated oil. In rickets a solution containing 0.01 
Gr. in 100 c.c. of cod-liver oil is recommended; 2—4 teaspoonfuls to 
be given each day. 1 In osteomalacia a one per cent, solution may be 
prescribed and 1-5 mg. phosphorus taken each day. 

1 This would be equivalent to .}-2 mg. of phosphorus daily, but as a matter of tact 
the phosphorated oil from which the prescription is filled contains much loss than one 
per cent., so that the dose actually taken probably seldom amounts to more than one 
milligram dailv. 



€06 INORGANIC SALTS, ACIDS AND BASKS. 

Rey found the lime excreted in the urine in rickets increased under 
the treatment with phosphorated cod-liver oil, much less under the oil 
alone, and not at all under phosphorus alone. He regards this as in- 
dicating an increased absorption of lime from the food. Other bone 
diseases, such as caries and ununited fractures, have also been treated 
with phosphorus occasionally, but the results have not been recorded 
in sufficient numbers to allow of any statement as to the efficacy of the 
treatment. 

Treatment of Phosphorus Poisoning. — Phosphorus is comparatively 
slowly absorbed from the alimentary canal, so that in the early stages 
an attempt ought to be made to remove it by emetics or the stomach 
tube, and by purges. Fats and oils must be avoided, as they tend to 
dissolve the poison and promote its absorption. Phosphorus has been 
found in the stools three days after its ingestion, and a sharp purge 
may therefore be of use up to this time. 

Another method of treatment is that aiming at the oxidation of the 
phosphorus in the stomach, or at the formation of unabsorbable com- 
pounds. It is stated that turpentine oil forms one or more compounds 
with phosphorus which are very much less poisonous than the origi- 
nal element, and possibly some oxidation of the phosphorus may be 
induced by the oil if it has not been recently distilled. The treat- 
ment of phosphorus poisoning with turpentine oil is therefore widely 
practised, but from the latest experiments (Busch) it seems entirely 
useless, for he found that animals succumbed to almost the same dose 
of phosphorus whether turpentine was given or not. Sulphate of cop- 
per is also recommended in phosphorus poisoning, a large dose being 
given first as an emetic, and afterwards smaller doses to form an insolu- 
ble compound, copper phosphide. Permanganate of potassium solu- 
tion, one per mille, has been recently advised to oxidize the phosphorus, 
while peroxide of hydrogen solution is of less value. In the secondary 
stnge alkalies are recommended in order to neutralize the excess of 
sarcolactic acid formed in the tissues. 

Phosphorus necrosis has to be treated surgically on the same princi- 
ples as other necroses of bone. 

Bibliography. 

Wegner. Virchow's Arch., lv., p. 11. 

Kassowitz. Ztschr. f. klin. Med., vii., p. 36. 

Sternberg. Ibid., xxii., p. 265. 

Stubenrauch. Arch. f. klin. Chir., lix., p. 144 ; lxi., p. 547. 

Jaf-obj. Zeitschr. f. physiol. Chem., xxx., p. 174. 

Miva u. Stoeltzer. Jahrb. f. Kinderheilkunde, xlvii., p. 153. 

Hey. Deutsch. med. Woch., 1895, p. 569. 

Stadelmann. Arch. f. exp. Path. u. Pharm., xxiv., p. 270. 

Aufreeht. Deutsch. Arch. f. klin. Med., xxiii., p. 331. 

Ackermann. Virchow's Arch., cxv., p. 216. 

Stolnickow. Arch. f. Anat. u. Phys., 1887. Supplement, p. 1. 

Schultze. Virchow's Arch., cii., p. 299. 

Meyer. Arch. f. exp. Path. u. Pharm., xiv., p. 313. 

Pal. Wien. klin. Woch., ix., p. 999. 

Sefmi. Arch. f. Pharmacie, cexvii., p. 253. 

Harnack Berl. klin. Woch., 1893, p. 1137. 



ARSENIC. 607 

Miura. Virchow's Arch., xcvi., p. 54. 

Bauer. Ztschr. f. Biol., vii., p. 63; xiv., p. 527. 

Schultzen u. Eiess. Annalen»der Charite, xv., p. 1. 

Fmenkel. Berl. klin. Woch., 1878, p. 265. Virchow's Arch., lxvii., p. 278. 

Falck. Arch. f. exp. Path. u. Pharrn., vii., p. 376. 

Sotnitschewsy. Ztschr. f. physiol. Chem., iii., p. 391. 

Fraenkel u. Rbhmann. Ibid., iv., p. 439. 

Leo. Ibid., ix., p. 469. 

Araki. Ibid., xvii., p. 311 ; xix., p. 422. 

M'dnzer. Deutsch. Arch. f. klin. Med., Iii., p. 199. 

Taussig. Arch. f. exp. Path. u. Pharm., xxx., p. 161. 

Hauser. Ibid., xxxvi., p. 165. 

Briliant. Ibid., xv., p. 439. 

Corinu. Ansiaux. Vierteljahr. f. ger. Med., 1894, i., pp. 80, 212. 

Hessler. Ibid., 1881, ii., p. 248, and 1882, p. 10. 

Lebert et Wyss. Arch. gen. de Med., 1868, ii., p. 257. 

Busch. Inaug. Diss., Dorpat, 1892. 

Athanasiu. Pfliiger's Arch., lxxiv.,p. 511. 

Taylor. Journ. of Exp. Med., iv., p. 399. 

Rosenfeld. Cong. f. inn. Med., xv., p. 427. 

Lindemann. Arch. f. exp. Path. u. Pharm., xli., p. 191. Ztschr. f. Biol., xxxix., 

Steinhaas. Ziegler's Beitriige z. path. Anatomie, xxii., p. 466. 
Monti, Slick, Frdnkel, Zweifel, Kassowitz. Wiener klin. Woch., 1901. 

XXXI. ARSENIC. 

Some of the less active preparations of arsenic, such as the sul- 
phides, Realgar (As 2 S 2 ) and Orpiment (As 2 S 3 ), have been known in 
therapeutics since the beginning of the Christian era, but this metal 
was brought into especial prominence in later times through the fre- 
quent use of the more dangerous oxides in criminal poisoning. Thus 
the notorious Aqua Tofana of the sixteenth and seventeenth centuries 
owed its activity to the presence of arsenic, and various arsenical com- 
pounds have been used up to the last few years more largely than al- 
most any other poison in suicide and homicide. This is to be ex- 
plained by their having been widely employed in the arts, and thus 
being readily accessible to all, and by the general recognition of their 
poisonous nature. Of late years intentional arsenic poisoning has be- 
come somewhat less common, though on the other hand, accidental 
poisoning is still met with not infrequently, especially in the chronic 
forms. Many of these chronic cases are extremely difficult to diagnose, 
and probably often pass unrecognized by the attending physician. In 
view of this fact it seems desirable that more stringent measures should 
be taken to reduce the use of arsenic in the arts, and especially to pre- 
vent its being brought in contact with food. The danger of the use 
of the green arsenical dyes, such as Scheele's Green (arsenite of cop- 
per), and Schweinfurt's Green, or Paris Green (arsenite and acetate 
of copper), is now generally recognized, but arsenic is still used in the 
preparation of other colors, and these may give rise to poisoning from 
the imperfect removal of the metal. It has also been used in dilute 
solution to preserve food, and a solution is often sprayed upon grape 
vines and other plants to preserve them from the attacks of insects. 
Poisoning has occurred from these sources and is difficult to diagnose, 
as it is in some cases impossible to find the means by which the arsenic 



608 INORGANIC SALTS, ACIDS AND BASES. 

entered the system. A widespread epidemic of poisoning in England 
in 1900 drew attention to a source of arsenic which had not up to that 
time received the attention it merited. Several thousands of persons 
suffered from arsenic being contained in cheap beers made from glu- 
cose, in the manufacture of which sulphuric acid had been employed. 
The sulphuric acid was formed from iron pyrites containing arsenic, 
and the poison was carried from the sulphuric acid with the glucose 
into the beer. Sulphuric acid is used in the manufacture of so many 
drugs, foods and other substances in constant use, that this intimation 
that it may convey arsenic into articles where its existence has not 
hitherto been suspected, is of the gravest importance. 

Metallic arsenic is insoluble in water, and passes through the alimen- 
tary canal for the most part unchanged and without action, but it is 
possible that small quantities may be oxidized to arsenious acid in the 
stomach and intestine under some conditions. Some symptoms have 
been observed when it is rubbed on the skin in a state of fine division, 
and these are probably due to its absorption in the form of an oxide. 
The characteristic " arsenic " action is induced by the salts of arsenious 
acid (AsO a H 3 ), and by its anhydride (As 2 O s ) which is often known as 
arsenic, and which exists in the tissues as arsenites. Arsenic action is 
therefore due, not to the element, but to the ion of arsenious acid. 
The anhydride and salts of arsenic acid (H 3 As0 4 ) cause similar symp- 
toms, but are less poisonous and act more slowly than those of arse- 
nious acid, and may probably owe their effects to the formation of 
arsenites in the tissues. 

The action being due to the ion and not to the element, it necessarily fol- 
lows that compounds from which the ion is not liberated, do not induce the 
arsenic action, or do so only when they are changed to bodies which can 
dissociate the arsenious acid ion. Thus organic arsenic combinations in 
which the metallic atom is directly attached to carbon are only feebly poison- 
ous, but in course of time seem to be changed to arsenious acid in the tissues, 
and then cause typical poisoning. The best known of these are cacodylic 
oxide ((CH 3 ) 2 As 2 0(CH 3 ) 2 ) and cacodylic acid ((CH 3 ) 2 AsOOH). Arsenical 
compounds of the aromatic series have also been examined pharmacologically 
and induce arsenic symptoms when given in large quantities. This poison- 
ous action is again due not to the undecomposed molecule, but to the arseni- 
ous acid derived from it, some of which is found excreted in the urine. 

Arsenious acid, which in the following pages will be taken as the 
representative of " arsenic " action, has a somewhat sweetish taste, and 
is therefore not so likely to be detected by the victim as many of the 
other poisons. 

Symptoms. — In large quantities arsenic very often causes no symp- 
toms for half an hour or more, but then the patient complains of a 
feeling of constriction in the throat, of difficulty in swallowing, and 
of discomfort in the stomach region. This soon increases to violent 
pain, and is- accompanied by vomiting, and later by watery diarrhoea. 
The stools are at first of ordinary diarrhoeic appearance, but later re- 
semble the " rice-water " stools of cholera, in that they consist almost 
entirely of minute shreds of disintegrated mucous membrane suspended 



ARSENIC. 609 

in a serous fluid ; sometimes, however, they are clear and gelatinous 
in appearance. In some cases, blood appears in the vomited matter 
and also in the stools, but this is not by any means an invariable fea- 
ture. The urine is diminished, or entirely suppressed, from the great 
amount of fluid eliminated by the stomach and bowel. These symp- 
toms from the alimentary tract are accompanied by giddiness, cramps 
in the muscles, headache, and soon by collapse, with cold, damp skin, 
pallor, feeble pulse and weak, sighing respiration ; this later passes into 
coma, and death follows with or without convulsions. In cases in 
which the dose is smaller than the fatal one, or in which much of the 
poison is eliminated by vomiting, the patient may recover without 
further symptoms than those already described. Frequently, how- 
ever, he recovers from the acute symptoms only to develop those of 
chronic arsenical poisoning. In some instances it is said that no 
symptoms are present except those of collapse and coma. In acute 
poisoning death may occur within 24 hours, but more frequently the 
patient lives for 2-4 days or longer, and then succumbs to exhaustion. 
The fatal dose is very uncertain, because arsenic is very insoluble, and 
much of the poison may be thrown up by vomiting, or pass out in the 
stools unabsorbed. Thus in some cases, recovery has followed after 
very large quantities, while in others about 0.1 G. (1 J- grs.) has proved 
fatal. 

Chronic Arsenic Poisoning may arise from a single large dose, the 
effects persisting for weeks or months after the ingestion and new symp- 
toms arising as the earlier ones disappear ; more frequently, however, 
it is induced by the prolonged absorption of small quantities. The 
milder symptoms may arise from its therapeutic use, but typical cases 
are generally due to the presence of arsenic in the form of dyes in wall 
paper or clothes, or in stuffed animals in the rooms inhabited by the 
victims, or to the constant handling of arsenical pigments and other 
compounds in mines and manufactories. Widespread poisoning has 
been observed from the use of wines containing arsenic at Hyeres in 
France, from milk diluted with arsenical water in London, and from 
beer in the Manchester district. In these last cases the arsenic was in 
solution, but it often seems to be inhaled in the form of fine dust, which 
falls from the walls or other objects. It has been suggested that the 
arsenic dyes are decomposed by microbes and the volatile arseniuretted 
hydrogen (AsH 3 ) inhaled, but there seems no reason to suppose that 
this is the case, and the inhalation of fine particles is a sufficient ex- 
planation. 

The symptoms of chronic arsenic poisoning, which are often very 
obscure, may be divided into three phases. In the first of these, the 
patient complains of weakness and languor, loss of appetite, some nausea 
and occasionally vomiting, with a sense of heaviness and discomfort in 
the stomach. Diarrhoea may be present, but is often absent, and in 
fact some constipation may occur. 

In the second phase the conjunctiva is often red and inflamed, and 
symptoms of coryza appear, with sneezing, hoarseness and coughing, 
39 



010 INORGANIC SALTS, ACIDS AND BASES. 

from a catarrhal condition of the mucous membranes of the nose and 
larynx. Some swelling of the liver and jaundice may occur, but these 
are not generally well marked. Skin eruptions of various forms — pap- 
ular, vesicular, or erythematous — are generally noted ; very often the 
epidermis falls off in fine brownish scales, or in tho hands and feet in 
large flakes (keratosis) ; a curious pigmentation is very common, the 
skin assuming a dark metallic color resembling in extreme forms that 
produced by rubbing a lead pencil upon it (arsenic melanosis). This 
pigmentation is much more marked in persons of dark complexion than 
in fair people in whom it may be indistinguishable from ordinary freck- 
les ; it generally disappears when the patient is removed from the poi- 
sonous atmosphere, but has been permanent in some cases. In pro- 
longed poisoning the eruptions may simulate almost any form of skin 
disease, and the hair and nails fall off. Herpes is not infrequently 
observed and points to nervous disturbances such as are prominent 
features in the next phase. 

These phases are not always distinct in cases of poisoning, and very 
often some of the symptoms of the second phase may appear before 
any marked disorder of the digestive tract. In the prolonged thera- 
peutic use of arsenic, the first indications of commencing poisoning are 
redness, suffusion and swelling of the conjunctiva and eyelids, and 
dryness of the nose and throat, as in coryza. On the other hand, in 
workmen exposed to arsenical dust, the first symptoms may arise from 
the skin or from bronchial irritation. 

The third phase is marked by disturbance of sensation and motion in 
localized areas, generally in the hands and feet (peripheral neuritis). 
It is often ushered in by intense persistent headache or by acute 
pain located around the knee, ankle or foot, less frequently in the 
wrist and hand. The patient complains of formication in the ex- 
tremities, and of the discomfort caused by the pressure of the bed- 
clothes on the feet and legs. The palms of the hands and the soles of 
the feet are often red, swollen and extremely sensitive to touch (ery- 
thromelalgia), and pressure on the muscles induces the most intense 
pain. Later, sensory paralysis may set in, especially in the extrem- 
ities, and the less acute sense of touch in the feet and hands induces 
symptoms resembling those of locomotor ataxia. The sensitiveness to 
heat and cold may be exaggerated or dulled, or sometimes heat is not 
appreciated, while cold causes intense pain. The sense of pain varies 
in different cases, in some being abnormally acute, in others deadened. 
These sensory disturbances are followed in severe poisoning by motor 
paralysis which generally appears in the extensor muscles of the toes, 
later in the peronei muscles. More rarely the flexor muscles of the leg 
and foot are involved, and in some cases the affection commences in the 
extensors of the hand and fingers. As a general rule the paralysis is 
confined to the extremities, but in some cases it has been found to in- 
vade the trunk. It is generally, but not invariably, symmetrical, and 
the muscles affected atrophy rapidly, and contract weakly to the gal- 
vanic shock, not at all to the faradic except in the beginning of the 



ARSENIC. 611 

affection. This lessened excitability of the muscles sometimes appears 
before the typical degeneration reaction is observed, but is then fol- 
lowed by it later. The muscles are abnormally excitable to mechanical 
stimulation, however, while the tendon reflexes are generally entirely 
absent. There is sometimes some difficulty experienced in diagnosing 
arsenic from lead paralysis, but in the former there is often a history 
of acute poisoning, while the latter is almost invariably due to pro- 
longed absorption. Disturbances of sensation are much more com- 
mon in arsenic than in lead palsy, and in the latter the forearm mus- 
cles are generally affected first, in the former those of the leg. In 
arsenic poisoning atrophy is said to occur much more rapidly, and 
there is no line on the gums. Another condition which presents still 
greater difficulties in diagnosis is alcoholic neuritis. But in the latter 
skin eruptions are extremely rare, coryza is not present, and there are 
generally more marked brain symptoms than in arsenical cases. In 
doubtful cases the urine and the hair of the patient should be tested for 
arsenic. 

Arsenic paralysis may appear as early as three days after an acute 
intoxication, but is commonly observed later and may occur only after 
3—4 weeks. Some authors have asserted that in chronic arsenic poi- 
soning there is a paralysis of the sexual powers (anaphrodisia), and 
ascribe this to an action on the nerves of the sexual organs, similar to 
that observed in the extremities, but this symptom is not by any 
means generally present, and, in fact, abnormal sexual excitement has 
been noted in some cases. 

In very prolonged arsenic poisoning the patient may sink into an 
apathetic, semi-idiotic condition, or may become epileptic. In most 
cases the symptoms slowly disappear when the poison is removed, but 
even slight paralysis may last for many years before it is entirely 
cured, and after complete degeneration of the muscles little improve- 
ment is to be expected. The contractures which follow are generally 
due to the unopposed action of the sound muscles, but sometimes arise 
from the shortening of the paralyzed ones. 

Arsenic poisoning generally occurs from the inhalation of particles 
of the drug, or from swallowing solutions or powders. But the same 
symptoms have been elicited in animals by subcutaneous or intravenous 
injection, and some cases of poisoning in men are recorded in which 
the arsenic gained entrance to the body through its application to burns 
or other surfaces denuded of skin, or from its application to mucous 
membranes, as in the vagina. 

Action. — The symptoms of arsenic poisoning, as far as the Alimen- 
tary Canal is concerned, resemble those of corrosive poisoning so closely 
that it was long supposed that arsenic had some destructive effect upon 
albumins, resembling that of the acids and corrosive metals. Many 
attempts to form a combination between proteids and arsenic have 
been made, but have proved fruitless ; arsenites and arsenious acid do 
not coagulate proteids or change them in any way, except when applied 
in such enormous quantities as never reach the stomach. 



612 INORGANIC SALTS, ACIDS AND BASES. 

The action of arsenic on the alimentary canal cannot be explained 
as due to any ordinary form of corrosion, therefore, although the symp- 
toms and the post-mortem appearances resemble in many points those 
of the corrosive poisons. Thus the mucous membrane of the stomach 
is generally found red and swollen, either in patches or throughout its 
whole extent. Haemorrhages into it are occasionally present, but are 
not by any means a constant feature, and little or no erosion can be 
made out as a general rule. The epithelial coat can be rubbed off 
very easily, and is found to be in a state of fatty degeneration. It 
sometimes resembles a false membrane and has been described as such, 
but closer examination shows it to consist almost entirely of the degen- 
erated epithelium. This destruction of the epithelium is often con- 
fined to particular parts of the organ, affecting the posterior wall 
chiefly in man. Where arsenic has been swallowed in powder, and 
has remained in contact with the wall for some time, the congestion is 
often more marked, and here even erosion may appear. In some cases 
no congestion of the stomach is met, the only lesion consisting in 
cloudy swelling and fatty degeneration of the gland-cells, similar to 
that mentioned under phosphorus. 

The intestine presents very similar appearances, the mucous mem- 
brane being swollen and congested, more especially around Peyer's 
patches. It contains a quantity of thin fluid with flakes of membrane, 
resembling exactly the rice-water stools of cholera, and in fact it may 
be difficult to distinguish the intestine of arsenic poisoning from that of 
cholera. Small particles of arsenic are often found in the stomach and 
bowel, even after profuse vomiting and purging. 

In some cases the redness and congestion extends up to the throat 
and causes a feeling of soreness in the mouth. 

The first explanation suggested for the action of arsenic on the ali- 
mentary tract, namely, the corrosive action of the drug, has been 
shown to be incorrect, for the same symptoms arise when arsenic is 
absorbed from the subcutaneous tissue, or from the broken skin. This 
does not entirely preclude the corrosive action, for arsenic, though ab- 
sorbed from the skin, may be excreted by the mucous membranes, and 
thus corrode them ; and, as a matter of fact, small quantities (up to a 
milligram) have been isolated from the stomach and intestines, when 
arsenic was injected intravenously in animals, but these are obviously 
insufficient to cause such violent symptoms. Besides, as has been 
stated, arsenic does not change proteids in solution as the corrosive 
poisons do, and cannot therefore elicit typical corrosion. Boehm 
and his pupils have suggested that the gastro-intestinal action of 
arsenic is due, not to any direct action on the epithelium, but to the 
vascular changes induced by it. They suppose that the extreme dila- 
tation of the intestinal vessels and capillaries gives rise to the conges- 
tion and swelling, and this in turn to the destruction of the lining 
membrane, perhaps by the exudation of fluid beneath the epithelium. 
This transudation of fluid is certainly in accord with the watery char- 
acter of the stools in arsenic poisoning, but the explanation does not 



ARSENIC. 613 

seem entirely satisfactory, for it fails to account for the fatty degener- 
ation and the cloudy swelling of the epithelium, which are in some 
cases the only lesions found here. The fatty degeneration is not con- 
fined to the stomach and bowel, but involves a number of other organs, 
although it is not as a general rule so widely distributed as in phos- 
phorus poisoning. Arsenic then must be considered to have a specific 
action in causing fatty degeneration of the epithelium of the stomach 
and intestine. This in itself is sufficient to explain many of the 
symptoms from these organs, although it may well be that the vascular 
action is the cause of the excess of fluid in the intestine, and in fact, 
the fatty degeneration alone is insufficient to explain this feature, which 
is absent in phosphorus poisoning. In cases of poisoning where the 
arsenic is taken by the mouth, and especially when large quantities of 
dry arsenious acid are swallowed, the specific action on the epithelium 
and the vascular action are probably intensified by the direct contact 
of the poison. Filehne is disposed to regard the corrosion of the 
stomach which is sometimes observed, as due to the digestion of the 
epithelium killed by arsenic, and not to the direct action of the 
poison. 

In therapeutic doses arsenic is said to increase the appetite and pro- 
mote digestion, an effect which may perhaps be due to the specific ac- 
tion on the epithelium, this in its milder forms proving of advantage 
to the organ, though in excess it leads to its degeneration. 

The action of arsenic on the Circulation has been investigated by 
several authors, who have obtained discordant results. In the frog 
the heart is slow and weak, eventually becomes irregular, and ceases 
in diastole after comparatively small doses ; the action seems to be a 
direct paralysis of the muscle. In the mammal the heart is less 
affected ; it is somewhat accelerated by very small doses injected in- 
travenously, but is slowed by larger ones, and the inhibitory mechan- 
ism does not seem to be altered. The blood-pressure is often increased 
at first, but soon falls after large doses. The cause of this fall has 
been a matter of dispute, but the most recent investigator (Pistorius) 
attempts to bring the results of his predecessors into accord by ex- 
plaining that the vaso-motor centre and later the splanchnic nerves lose 
their control over the vessels. When the pressure begins to fall, it 
may be restored by stimulation of the vaso-motor centre, but this loses 
its effect later, although direct stimulation of the splanchnic nerves 
still increases the tension. Still later the splanchnics lose their action 
through paralysis of their ends, or of the vascular walls, while the 
other vaso-constrictor nerves are still capable of narrowing the vessels ; 
for instance stimulation of the cervical sympathetic still causes pallor 
of the ear, so that this action of the drug seems to be confined to the 
splanchnic area. The dilation of the mesenteric vessels leads to very 
marked congestion of the stomach and bowel, and along with the les- 
sened efficiency of the heart reduces the blood-pressure to zero. Some 
evidence has been brought forward that under arsenic the capillaries 
permit the passage of fluid into the tissues more readily than normally ; 



614 INORGANIC SALTS, ACIDS AND BASES. 

this may explain the appearance of oedema in cases of poisoning and 
also the large amount of fluid in the stools and vomited matter. 

The Respiration is somewhat accelerated at first by the intravenous 
injection of small quantities of arsenic, but afterwards returns to its 
normal rhythm. In cases of poisoning in man the respiration does 
not seem to be much affected until late, but it ceases before the heart, 
probably from the exhaustion and low blood-pressure, and not from 
any specific action on the centre. 

The action of arsenic on the Central Nervous System has been re- 
peatedly examined. A descending paralysis is elicited in the frog, the 
animal first losing its spontaneous movements, and then its reflexes, 
and the terminations of the motor nerves being involved only very late 
in the intoxication. There is no question that the brain, spinal cord 
and nerve ends are directly acted on in these animals, for paralysis is 
elicited by arsenic much sooner than by arrest of the circulation by 
excision of the heart. In mammals there are generally no certain in- 
dications of direct action on the nervous system in acute poisoning, 
for the weakness and prostration, and the final loss of consciousness 
and coma may be attributed to the exhaustion from the gastrointes- 
tinal effects rather than to the centres being immediately affected. At 
the same time the acceleration of the respiration in the beginning of 
the intoxication, and the paralysis of the vaso-motor centres, would 
seem to point to a direct action on the medulla oblongata. 

The pathology of the nervous disturbances observed in chronic poi- 
soning, and often after a single large but not immediately fatal dose, is 
still obscure, and probably bears no relation to the symptoms observed 
in animals in acute poisoning. In many cases of paralysis, there is 
distinct tenderness along the course of the nerve trunks, which would 
suggest peripheral neuritis as the cause. Kreyssig could find no altera- 
tions in the spinal cord in cases of poisoning in animals except occa- 
sional haemorrhages, which did not seem to be of consequence. Jaschke 
and Alexander observed peripheral neuritis in animals, and the ques- 
tion therefore seemed decided in favor of the peripheral origin of the 
symptoms. More recently, however, in two autopsies of persons suffer- 
ing from arsenical paralysis, undoubted lesions of the spinal cord have 
been described. The symptoms point so unmistakably to peripheral 
neuritis as the cause, however, that the almost universal opinion is 
that the nerve fibres are the primary point of attack, although in 
severe cases the affection may involve the nerve cells in the cord in 
addition. 

The peripheral nerves and the muscles are little affected by arsenic in 
acute poisoning ; but the muscles of a frog poisoned with arsenic are found 
to lose their irritability somewhat sooner than those of one whose circulation 
and central nervous system have been destroyed, so that the poison has some 
deleterious effect on them also. 

The unbroken Skin is not affected by arsenic, unless when it is ap- 
plied repeatedly or allowed to remain in contact with it for some time,. 



ARSENIC. 615 

when it may give rise to redness, pustules or vesicles and later to vio- 
lent erysipelatoid inflammation. It has not, however, any such cor- 
rosive action on the skin as is possessed by strong acids, and the sub- 
cutaneous injection of arsenic is said not to be painful. It is more 
active when applied to denuded surfaces and to the mucous mem- 
branes, destroying them to some depth and causing acute pain, but 
even here it acts more slowly than ordinary caustics. It seems to act 
only upon living cells, and unlike acids and alkalies, forms no combi- 
nations with the dead tissues. The local effects of arsenic on the skin 
are seen only in workmen handling arsenic, as in color factories, in 
which affections of the skin of the face, hands and scrotum are by no 
means rare. 

In arsenic poisoning skin eruptions are common, and may be due in 
part to circulatory disorders, but are to be ascribed for the most part 
to the direct action of the drug on the skin. Arsenic has been found 
in appreciable amount in the hair, epidermal scales and in the fluid of 
a blister in patients treated with it, and changes in the condition of 
the skin in animals have also been observed. Thus Ringer found the 
epidermis of the frog peel off with great ease when it was poisoned 
with arsenic, and Nunn ascribes this to the softening of the protoplasm 
of the deeper cells of the epidermis ; analogous changes have been ob- 
served in the cornea. 

The melanosis of arsenic poisoning seems to be due to the deposi- 
tion not of an arsenical compound, but of some organic product in the 
deeper layers of the corium. The symptoms of irritation of the mu- 
cous membranes of the eye, nose and larynx are ascribed to the ex- 
cretion of arsenic on these surfaces, and are analogous to the skin 
eruptions. 

The action of arsenic on The Blood is still obscure, although it is fre- 
quently prescribed in various forms of anaemia. In chlorosis and in 
normal persons, it is said to diminish the number of the red corpuscles, 
but not to alter the total haemoglobin of the blood. In a case of 
pernicious anaemia recently examined by Engel, it was found that ar- 
senic increased the number of young newly formed red cells while the 
number of more mature corpuscles was diminished. Bettmann states 
that in subacute poisoning in rabbits, the red cells and haemoglobin are 
diminished, and nucleated red cells appear in the blood in some num- 
ber ; he holds that arsenic acts on the blood, and also on the blood- 
forming organs. Stockman and Greig found the blood cells and 
haemoglobin unaltered by arsenic in normal animals, but describe the 
bone-marrow as evidently in a state of unusual activity, indicated by 
its increased vascularity, greater number of red blood corpuscles and 
lessened fat cells. Silbermann asserts that arsenic tends to induce 
widespread intravascular coagulation, which leads to a fall in the 
blood-pressure, anaemia and other disorders. This assertion has been 
denied by Falkenberg, but has been supported by the experiments of 
Heinz, who finds that arsenic induces not ordinary coagulation, but 
thrombi formed primarily of blood plates, and attributes to this throm- 



616 INORGANIC SALTS, ACIDS AND BASKS. 

bosis the haemorrhages and subsequent ulceration which are sometimes 
observed in the walls of the stomach and intestine and elsewhere. 

In some cases of arsenic poisoning Fever is observed ; this does not 
seem due to any specific action of the drug but to the inflammation of 
the mucous membranes and the skin. 

The Metabolism is affected by a poisonous dose of arsenic in the 
same way as by phosphorus, but the alteration is not generallv so 
marked and is liable to be overlooked, owing to the more intense action 
on the alimentary canal. The nitrogen of the urine is considerably 
greater than that of inanition, but it is not quite clear whether this 
is due to an increase in the urea or to other nitrogenous substances. 
The ammonia is probably augmented, for a considerable amount of 
lactic acid has been derived from the urine, and the alkalinity of the 
blood is reduced owing to the formation of this acid in excess. The 
glycogen of the liver disappears entirely, and the liver seems incapable 
of forming it from the sugar of the food. Lesion of the medulla 
oblongata (diabetes puncture) does not cause glycosuria after arsenic, 
but curara and other drugs are still capable of eliciting this symptom. 
The fatty degeneration of the epithelium of the stomach and intestine 
has been mentioned already, but this alteration is not confined to these 
tissues, being found in the liver and kidney, in the muscle cells of the 
heart, blood vessels and striated muscles, and in the lining epithelium 
of the alveoli of the lungs. Small necrotic foci have been observed 
by Wolkow in the liver, along with signs of active division of the 
parenchymatous cells, as in phosphorus poisoning. 

Many of these changes admit of the same explanation as that given 
in phosphorus poisoning, namely, that arsenic lessens the oxidation of 
the tissues and causes fatty degeneration of the cells of various organs ; 
it may also increase the waste of the proteids of the body directly, 
but the increase in the nitrogen of the urine may perhaps be sec- 
ondary to the other features. Attempts have been made to demonstrate 
the lessened oxidation by estimating the respiratory gases, but here, 
as in phosphorus, no satisfactory results can be obtained by this method, 
owing to the slow progress of the intoxication, and to the diminished 
movement and retarded digestion ; these in themselves are sufficient to 
cause a marked fall in the output of carbonic acid and in the absorp- 
tion of oxygen, without any direct action on the tissue cells. The 
metabolism is less affected by arsenic than by phosphorus, however, 
for the fatty degeneration is less marked and less lactic acid is ex- 
creted. Nencki and Sieber have also shown that benzol can be oxi- 
dized to phenol in animals poisoned with arsenic, while in phosphorus 
poisoning the tissues are unable to effect this. 

The fatty degeneration may have the same results as in phosphorus 
poisoning. The liver is somewhat enlarged and the pressure on the 
bile ducts prevents the escape of bile into the intestine, and thus 
induces jaundice and the appearance of bile pigments and bile acid in 
the urine. Jaundice is seldom, however, a very marked feature in 
arsenic poisoning, and is often entirely absent. 



ARSENIC. 617 

The prolonged administration of arsenic in quantities insufficient to 
produce chronic poisoning is reputed to have some effect on the 
Growth and Nutrition. It is difficult to obtain accurate data in regard 
to this point, and while the improvement in nutrition is attested by a 
number of independent observers, other equally careful investigators 
have not been able to confirm their results. Gies treated some of a 
litter of young rabbits with arsenic in minute doses for several weeks, 
and found that they weighed more, and were larger in every way than 
the untreated animals ; the subcutaneous fat was much greater in 
amount, the bones were longer, and the muscles more developed. The 
long bones presented the appearance described by Wegner under phos- 
phorus treatment, being longer and containing more dense bone both 
in the shaft and the epiphyses. Female rabbits treated with arsenic 
bore young of abnormal size and weight ; Gies, in fact, supposes that 
their size caused difficulties in their passage through the pelvis, for 
they were all born dead. Several other observers have described a 
more rapid growth and greater activity in young animals treated with 
arsenic, and an increase in weight is often noted in man. On the 
other hand Stockman and Greig observed no change in the growth of 
animals under prolonged treatment with arsenic, and found that the only 
tissues affected were the growing bones, which appeared denser than usual. 

The improvement in nutrition has not been explained, though a slight 
decrease in the nitrogenous excretion, and in the amount of nitrogen 
in the stools has been noted by Weiske, who holds that more of the 
food is utilized by the digestive apparatus, and at the same time, less 
proteid is decomposed in the tissues. The change in the amount of 
nitrogen excreted is so small, however, that doubt may be entertained 
whether it may not be due to unavoidable errors in the estimation, and 
other investigators have been unable to detect any alteration attribut- 
able to the drug. Fresh investigation of this point is thus required 
before certainty can be reached regarding the effects on the nutrition, 
and still more regarding the explanation of the alterations. 

When small quantities of arsenic are taken habitually, Tolerance is 
established, and the dose may be gradually increased until it far ex- 
ceeds that which would be poisonous in ordinary persons. This is 
the explanation of arsenic-eating which is known to exist in different 
parts of the world, but which is most widespread and best known in 
Styria and the Tyrol. The peasants there indulge in the poison habit- 
ually, and believe that it enables them to work better, and in particular 
to climb the mountains with less effort and less respiratory distress. 
They also credit it with improving their complexions and general ap- 
pearance, and give it to their horses in order to render their coats more 
smooth and glossy, and to make them stronger and fatter. Doubt was 
formerly entertained as to the truth of the statements made regarding 
the doses used by these people, but this was definitely settled by lvnapp, 
who administered 0.4 G. (7 grs.) of arsenious acid to one of the peas- 
ants at Graz without inducing any effects whatsoever. Large quanti- 
ties of arsenic have also been isolated from the urine of arsenic eaters, 



618 INORGANIC SALTS, ACIDS AND BASKS. 

showing that much of the drug is absorbed. Arsenic-eating is said to 
be indulged in to a considerable extent by young women in some coun- 
tries with the object of improving the complexion and figure, and cases 
of arsenic habit have been described in different parts of America and 
elsewhere. As far as can be observed the habit is not deleterious, for 
the Styrian peasants live to old age, and no symptoms attributable to 
the poison have been noted. As a general rule large doses are taken 
once or twice a week, and no fluid is swallowed for some time after- 
wards, so that some of the poison may pass through the bowel unab- 
sorbed. No tolerance for arsenic has been established in animals, even 
by prolonged treatment with minute doses. 

As a contrast to the Styrian peasants, the miners of Reichenstein 
may be mentioned, who are constantly exposed to arsenic owing to its 
being contained in large quantities in the ore. These people are de- 
scribed by Geyer as shortlived, very subject in childhood to severe 
rickets and in adult life to dropsies and respiratory diseases ; they 
offer little resistance to microbial infection and frequently present the 
skin and nervous symptoms of arsenic poisoning. Why arsenic should 
be beneficial or at any rate harmless at Graz, and so deleterious in 
Reichenstein, it is impossible to state at present. 

Arsenic is Excreted for the most part in the urine, to a much smaller 
extent in the stomach and bowel and along the respiratory mucous 
membranes. Traces are eliminated in the skin secretions, in the hair, 
and in the milk, and fatal intoxication has been observed in a child 
from the milk of its mother, who was suffering from acute poisoning. 
In the urine arsenic appears in part in organic combinations, in part, 
according to Selmi, in the form of a volatile organic base, which is in- 
tensely poisonous and causes convulsions in frogs. Arsenic is only 
slowly excreted ; it is stated to have been detected in the urine 2-3 
months after its administration, but it has been shown to occur in the 
urine of a number of persons who presented no signs of poisoning and 
had not been treated with arsenic, so that it is possible that in those 
cases of slow elimination the arsenic of the urine did not arise from the 
single administration, but from its subsequent absorption from some 
other source, such as the water or air. There is no question, however, 
that it remains in the system longer than many other poisons. It is 
probable that the effects, especially the paralysis, last long after the 
drug has been excreted, lesions having been induced which are only 
slowly recovered from. 

Arsenic is found in largest quantity in the liver after absorption, but 
is also deposited in the kidney, in the walls of the stomach and intes- 
tine, and in the spleen and lungs. Much smaller quantities are found 
in the muscles and in the nervous tissues, which were formerly sup- 
posed to contain more than the liver. It is stated that in cases of 
poisoning arsenic is found in the white matter of the brain in much 
larger proportion than in the cortex. In the blood, most of the 
arsenic is said to be contained in the blood-cells, comparatively little 
being free in the plasma. Arsenic has been detected in the cancellous 



ARSENIC. 619 

bones of the skull and vertebra?, after it had disappeared from all the 
other organs. 

Arsenic is poisonous to many of the lower forms of life, as well as to the 
vertebrates ; thus it has been found that its presence in comparatively dilute 
solution (one part of arsenious acid in 30,000 parts of water) hinders the 
development of, and eventually kills algae and the seeds of the higher plants. 
On the other hand, moulds grow abundantly in a solution of arsenite of 
potash (1 per cent.) containing some organic matter, and the alcoholic fer- 
mentation proceeds in the presence of arsenic, although it is somewhat re- 
tarded at first ; very dilute solutions of arsenic even accelerate the fermen- 
tation, as is true of most other antiseptics. Arsenious acid is only about 
one-tenth as strong an antiseptic as perchloride of mercury, and the spores 
of anthrax are destroyed only after ten days in a one per mille solution. It 
has therefore a greater antiseptic power than many of the other acids, but 
compared with its action on the higher forms of life, it is but slightly 
poisonous to the fungi. It seems to have no effect on the activity of the 
ferments, such as pepsin, myrosin and emulsin. 

The arsenates are much less harmful to lowly organized forms, for seeds 
and algae as well as moulds grow in a neutral solution abundantly, and even 
the infusoria do not seem injured by it to any marked degree. Apparently 
these plants and animals are incapable of reducing it to arsenious acid, and 
are therefore not more affected by it than by other acids. 

The bodies of persons poisoned with arsenic are said to remain undecom- 
posed for a remarkably long time, and to tend to become mummified. The 
statement is still disputed, but is vouched for by a number of authorities. 
It is certainly not invariably the case, and little weight is to be laid upon 
mummification in determining whether arsenic poisoning was the cause of 
death in exhumed persons. 

No account of the pharmacology of arsenic would be complete without 
mention of the theory advanced by Binz and Schulz to explain its action. 
They suppose that arsenious acid is oxidized to arsenic acid by the living tis- 
sues, and the arsenic acid again reduced to arsenious. In this way oxygen is 
alternately withdrawn from, and supplied to the protoplasm, and this alter- 
nate reduction and oxidation they suppose to be the essential feature of the 
action of arsenic. The grounds on which this explanation is based must be 
sought in the numerous papers on the subject by these authors, and it may 
suffice here to state that while arsenic acid appears to be reduced, and 
arsenious acid oxidized in the tissues, these processes are probably only 
gradual. Otherwise it would be difficult to explain how arsenious acid is so 
much more poisonous than arsenic acid, for if the latter were readily re- 
duced to arsenious acid it would be equally toxic. 

Arsenic and phosphorus are included in one group in chemistry, and 
their effects on living organisms present sufficient resemblance to jus- 
tify their association in the pharmacological system. The mucous 
membranes and the skin are more affected by arsenic, however, and 
the circulation is more rapidly depressed, while the fatty degeneration 
of the protoplasm of the vertebrates is much more prominent in phos- 
phorus poisoning. . The differences between their effects are more in 
degree than in kind, and there seems no question that their ultimate 
action on protoplasm is of the same nature. It is to be noted, how- 
ever, that there is no reason to suppose that phosphorus owes its 
action to any of its numerous compounds with oxygen, while it is 
probable that the oxides of arsenic alone are capable of modifying 
vital functions. 



620 TSORGANIC SALTS, ACIDS AND BASES. 

The Sulphur Compounds of arsenic are entirely insoluble and are therefore 
not absorbed as such, but it seems likely that small quantities of arsenious 
acid are formed from them in the intestine by microbes. Commercial orpi- 
ment often contains large amounts of arsenious acid. 

Arseniuretted Hydrogen (AsH 3 ) is an exceedingly poisonous gas, which 
has caused a number of fatal accidents from being inhaled accidentally in 
chemical laboratories. One source of danger is the liberation of hydrogen 
from acids by the action of zinc, which often contains arsenic and therefore 
gives rise to this gas. It differs entirely from' the oxides of arsenic in its ac- 
tion, and there is no reason to suppose that it forms these in the body. Pos- 
sibly traces of arseniuretted hydrogen are formed from arsenious acid in the 
intestine, but in insufficient quantities to have any appreciable effect. Ar- 
seniuretted hydrogen acts as a molecule, AsH 3 , arsenites as ions, and the 
fact that both molecule and ion contain an atom of arsenic, does not neces- 
sarily entail that their effects shall bear any resemblance. 

Arseniuretted hydrogen acts by destroying the red corpuscles of the blood, 
and induces intense headache, nausea and vomiting, prostration and faint- 
ing fits, cyanosis and collapse. Haemoglobin, methaemoglobin, haematin and 
occasionally blood are passed in the urine, and more rarely the stools contain 
blood. Sometimes the urine is entirely suppressed from the tubules being 
plugged with blood cells and debris, and intense icterus appears from the 
formation of excess of bile pigment from the haemoglobin of the disinte- 
grated corpuscles. (Edema of the lungs or sudden failure of the heart is the 
cause of death. Some of the gas is excreted by the lungs, and may be rec- 
ognized by its garlic odor, and some arsenic appears in the urine, but it is 
not known in what form. 

Preparations. 

Acidum Arsenosum (U. S. P.), Acidum Arseniosum (B. P.) (As 2 3 ), 
arsenous or arsenious acid anhydride, white arsenic, ratsbane, forms a white 
powder, or opaque, porcelain-like masses, or a transparent, amorphous sur- 
face like glass. It dissolves slowly in cold water, the glassy variety requir- 
ing about thirty, the porcelain about eighty parts of water. It is almost 
tasteless and has no odor. 1-5 mgs. (eV-iV g r -)> iu pill or solution, after 
meals. The "Asiatic" pill consists of arsenic, black pepper and liquorice. 

Liquor Acidi Arsenosi (U. S. P.), Liquor Arsenici Hydrochlorides (B. P.), a 
one per cent, solution of arsenous acid acidulated with hydrochloric acid. • 
0.05-0.5 c.c. (1-8 mins.), 3-5 drops three times daily, after meals. 

Liquor Potassii Arsenitis (U. S. P.), Liquor Arsenicalis (B. P.), Fow- 
ler's solution, contains one per cent, of arsenous acid neutralized with bicar- 
bonate of potash, to which compound tincture of lavender is added to give 
color and flavor. 0.05-0.5 c.c. (1-8 mins.), 3-5 drops three times daily, 
after meals. 

Sodii Arsenas (U. S. P.) (Na 2 HAs0 4 + ^H 2 0) forms colorless, odorless crys- 
tals, very soluble in water, with a mild, alkaline taste. 1-5 mgs. (eV-rV g r -)- 

Sodii Arsenas (B. P.) (Na 2 HAs0 4 ) is prepared from the ordinary arsenate 
(U. S. P.) by driving off the water of crystallization, and forms a white 
powder, ^-to gr. 

Liquor Sodii Arsenatis (U. S. P., B. P.), Pearson's solution, a one per cent, 
solution of the sodium arsenate of the respective pharmacopoeias. 0.05-0.5 
c.c. (1-8 mins.). 

Arseni Iodidum (IT. S. P.), Arsenii Lodidum (B. P.) (Asl 3 ), glossy, orange- 
red crystals with an iodine odor and slowly giving off iodine in the air ; it is 
soluble in 7 parts of water, but the solution soon decomposes into arsenous 
and hydriodic acids. 3-10 mgs. (i -l gr.). 

Liquor Arseni (Arsenii, B. P.) et Hydrargyri Iodidi (U. S. P., B. P.), 
Donovan's solution, contains one per cent, of arsenic iodide and one per 
cent, of red mercuric iodide. This solution is clear and yellowish, without 
odor, but with a harsh metallic taste. 0.3-1.3 c.c. (5-20 mins.), after meals. 



ARSENIC. 621 

Ferri Arsenas. (See Iron.) 

Some mineral waters contain arsenic, that of Levico as much as 8 mgs. 
per litre. 

Therapeutic Uses. — The action of arsenic as ascertained from ex- 
periments on the lower animals and from cases of poisoning in man 
throws little light on its use in therapeutics, and so little is known of 
the pathology of most of the conditions in which it is found of benefit, 
that no attempt can be made to bring the two series of observations 
into relation. 

Arsenious acid has been used externally as a caustic, formerly in 
various forms of malignant disease, more recently in lupus, in which 
it is said to destroy the diseased surface while leaving the healthy skin 
unaffected. It has been superseded, however, by the introduction of 
surgical measures, such as scraping with the sharp spoon. Arsenic in 
substance is still used in dentistry to destroy the pulp in decayed teeth. 

Internally arsenic is used in malarial disease, especially in invete- 
rate cases in which there in much cachexia. In acute cases it is also 
of benefit, but is much less certain in its effects than quinine, and it is 
very questionable whether it acts on the malarial organism, for its effi- 
cacy often seems due rather to its improving the general nutrition and 
lessening the cachexia and wasting. Many authorities, in fact, depre- 
cate the use of arsenic in acute malaria, and would limit its use to the 
cachexia of old disease, while others advise its use with iron in ordinary 
cases, after the acute stage has been successfully treated with quinine. 

Arsenic has also been used with benefit in neuralgia, especially when 
it assumes a periodic character, and in chronic rheumatism, but in many 
gases no definite improvement follows, and the conditions under which 
it is of value cannot be more accurately defined at the present time. 
Old cases of chorea often improve under arsenic, which may imply 
some action on the central nervous system, although, as has been 
stated, little alteration in the nervous functions is observed in ani- 
mals except under very large doses. Asthma has also been treated 
with arsenic given by the stomach, or by the inhalation of arsenic 
from smoking cigarettes made with arsenical paper. 

In pernicious anaemia, arsenic is said to be beneficial, but the im- 
provement is only temporary. Many forms of skin disease are treated 
with arsenic, some of them with the happiest results. Thus in psoria- 
sis, chronic eczema and lichen ruber, marked improvement or complete 
recovery often dates from the beginning of the arsenic treatment. It 
is generally advised only in the chronic forms, and is said to be posi- 
tively deleterious during the earlier stages of rapid cell proliferation. 

In lymphoma, arsenic has been given internally and also by direct 
injection into the tumors, and often, though not by any means inva- 
riably, proves of value. Various other forms of leuca?mia have been 
treated with less success. 

The action of arsenic in reducing the glycogen of the liver suggested 
its use in diabetes, but most reliable authorities have failed to obtain 
satisfactory results. 



622 INORGANIC SALTS, ACIDS AND BASKS. 

Arsenic is in the great majority of cases prescribed in the form of 
Fowler's solution. It is generally advisable to commence with small 
doses, and to increase them as tolerance is developed, but some au- 
thorities advise large doses from the outset. Arsenic is always pre- 
scribed to be taken after meals, in order to avoid any possible action 
on the digestion. 1 Several authors have recommended the hypodermic 
injection of Fowler's solution diluted with two parts of water. (Dose 
0.5 c.c., 8 mins.) Arsenic is contraindicated in cases of irritation of 
the stomach and bowel, and is generally avoided during acute fever, 
except in malaria. 

If symptoms of chronic poisoning begin to assert themselves, the 
drug must be discontinued at once. The first symptoms are generally 
disordered digestion, loss of appetite and discomfort in the stomach 
region, a feeling of constriction in the throat and redness and swelling 
of the conjunctiva and eyelids. 

In Acute Arsenic Poisoning the stomach ought to be emptied at once 
by means of the stomach tube or by an emetic (apomorphine). The 
stomach washing is to be continued for some time, as arsenic is very 
insoluble. Various chemical antidotes have been advised, chiefly with, 
the view of forming the insoluble arsenites of iron or magnesia. The 
best preparation of iron is the hydrate, which must be recently pre- 
cipitated, as it forms granules when it is allowed to stand and is then 
much less efficient ; it may be prepared in an emergency by adding 
magnesia to a solution of iron sulphate. Magnesia alone may be used, 
and for this purpose magnesia levis is preferable, given shaken up 
with water. The mixture of iron sulphate and magnesia has the ad- 
vantage of containing in addition to the hydrate and magnesia, the 
cathartic sulphate of magnesium, which tends to remove from the in- 
testine any arsenic which may have already passed into it. The anti- 
dote should be given in large quantities at intervals as long as the 
acute symptoms persist. 

The collapse is treated by the ordinary measures, warmth and stimu- 
lants, such as caffeine and digitalis. In chronic poisoning, the paraly- 
sis is treated by stimulating the muscles with the galvanic current, the 
other symptoms by suitable general treatment. 

Bibliography. 

A very complete account of the action of arsenic is given by Wertheimer in Richet's 
Dictionnaire de Physiologie, i., p. 674. Among the numberless papers on Arsenic the 
following may be mentioned : 

Boehmu. Unterberger. Arch. f. exp. Path. u. Pharm., ii., p. 89. 

Johannsohn. Ibid., ii., p. 99. 

Pixtorius. Ibid., xvi., p. 188. 

Kossel. Ibid., v., p. 128. 

Gies. Ibid., viii., p. 175. 

Saikowsky. Virchow's Arch., xxxiv., p. 73. 

Sklarek. Arch. f. Anat. u. Phys., 1866, p. 481. 

1 Cacodylate of sodium, in doses of 0.05 G. (1 gr. ), has recently been recom- 
mended as a substitute for the ordinary arsenical preparations. It appears to be ex- 
creted for the most part unchanged but a small percentage is reduced and this has 
the same effect as the more commonly used preparation (Heffter). 



ARSENIC. 623 

Vryens. Arch, de Physiol., 1881, p. 780. 
Falck. Arch. f. exp. Path. u. Pharm., vii., p. 394. 
Meyer. Ibid., xiv., p. 329. 
Filehne. Virchow' s Arch. , lxxxiii., p. 1. 

Schulz u. Binz. Arch. f. exp. Path. u. Pharm., xi., pp. 131, 200 ; xiii., p. 256 ; 
xiv., p. 345 ; xv., p. 322 ; xxxvi., p. 275 ; xxxviii., p. 259 ; xli., p. 179. 
Husemann. Deutsch. med. Woch., 1892, p. 1081. 
Lesser. Virchow' s Arch., lxxiii. and lxxiv. 
Dogiel. Pfl tiger's Arch., xxiv., p. 328. 
Araki. Ztschr. f. phys. Chem., xvii., p. 331 ; xix., p. 442. 
Heffter. Arch. f. exp. Path. u. Pharm., xxxi., p. 257. 
Siibermann. Virchow' s Arch., cxvii., p. 288. 
Heinz. Ibid., cxxvi., p. 495. 
Wolkow. Ibid., cxxvii., p. 477. 
Smetana. Wien. klin. Woch., 1897, p. 903. 
Engel. Virchow' s Arch., cxxxv., p. 369. 
Selmi. Virchow -Hirsch. Jahsresber., 1881, i., p. 413. 
Imbert-Gourbeyre. Des suites de l'empoisonnement arsenical. Paris, 1881. 
Brouardel et Pouchet. Bull, de l'acad. de med., 1889, p. 915. 
Dana. Brain, ix., p. 456. 

Seeligmuller. Deutsch. med. Woch., 1881, p. 185. 
BaCosta. Philadelp. Med. Times, 1881, p. 385. 
Krehl. Deutsch. Arch. f. klin. Med., xli v., p. 325. 
Marik. Wien. klin. Woch., 1891, p. 565. 
Kovacs. Wien. med. Woch., 1887. 
Kreyssig. Virchow' s Arch., cii., p. 286. 
Huber. Ztschr. f. klin. Med., xiv., p. 444. 
Alexander. Habilitation- Thesis, Breslau, 1889. 
Erlieki u. Bybalkin. Arch. f. Psychiatrie, xxiii., p. 861. 
Schlosser. Inaug. Diss., Basel, 1896. 
Ringer and Murrell. Journ. of Physiol., i., p. 213. 
Nunn. Ibid., i., p. 247. 

Gornil et Brault. Journ. de l'anat., xviii., p. 1. 
Putnam. Boston Medical and Surgical Journal, cxx., p. 235. 
Bettmann. Ziegler's Beitrage, xxiii., p. 377. 
Loew. Pfl tiger's Arch., xl., p. 444. 
Chittenden. Maly's Jahresbericht, 1885, p. 277. 
Stockman and Greig. Journ. of Physiol., xxiii., p. 376. 
Geyer. Arch. f. Dermat. u. Syph., xliii.,p. 221. 

Reynolds and others. Lancet and British Med. Journal, 1900, ii., and 1901, i. and ii. 
Morishima. Arch, internat. de Pharmocodyn., vii., p. 65. 
Heffter. Arch. f. exp. Path. u. Pharm., xlvi., p. 230. (Cacodylates. ) 

On arseniuretted hydrogen. 

Stadelmann. Arch. f. exp. Path. u. Pharm., xvi., p. 221. 

Minkowski u. Naunyn. Ibid., xxi., p. 14. 

Waechter. Vierteljahr. f. gericht. Med., xxviii., p. 251. 



PART IV. 

THE HEAVY METALS. 
HEAVY METALS. 

A large number of important drugs, belonging to the chemical 
series of heavy metals resemble each other so closely in their action in 
living organisms that they may be readily grouped together in a divi- 
sion of the pharmacological system. Some authors include in this 
series arsenic and antimony, but the former presents so many analogies 
to phosphorus in its effects that it is preferable to treat it apart from 
the heavy metals. Antimony is certainly as closely related to arsenic 
as to this group, and may be regarded as a connecting link between 
them. 

The metals as such do not induce any symptoms except from their 
mechanical properties. Thus mercury may be swallowed in large 
quantities without causing mercurial poisoning, and silver or copper 
coins are equally devoid of effect as poisons. They are active only 
when they are capable of dissociation into ions of the metal or of an 
oxide. Thus potassium ferrocyanide does not cause any symptoms of 
iron poisoning when it is injected into a vein, because the iron passes 
through the body undissociated, and any effects are due to the ferrocya- 
nide ion and not to the iron. In the same way compounds of the metals 
with ethyl and methyl, such as lead triethyl, have an action quite dif- 
ferent from that of lead, as long as they remain undecomposed in the 
tissues, but eventually induce metallic poisoning, as they are broken 
up into bodies from which the lead or lead oxide ion can be dissociated. 

The action of the heavy metals consists of two parts, the local effects 
induced at the point of application, and the general effects which fol- 
low the absorption of the poison into the blood and tissues. Either of 
these may be produced alone by suitable preparations and modes of 
administration, and they are to be regarded as entirely independent of 
each other. 

The Local Action of the heavy metal series is due to the formation 
of proteid combinations. When the salt of a heavy metal is added to 
a solution of egg albumin, or of similar proteid, a precipitate is at 
once formed of metallic albuminate. The proteids apparently play the 
role of acids, forming insoluble salts with the metals, but these salts 
are not generally of definite chemical composition, for the percentage 
of metal contained in the albuminate usually varies within wide 
limits; in some cases, however, definite compounds have been formed. 
40 625 



026 THE HEAVY METALS. 

The albumin displaces the original acid of the salt, which may be 
entirely removed by prolonged washing. The albuminates of the 
metals are insoluble in water, but some of them, notably that of 
mercury, are soluble in excess of proteid, and most of them may be 
dissolved in solutions of neutral salts such as chloride of sodium. In 
the albuminates formed by the addition of salts to proteid solutions, the 
metals are combined in the same way as in inorganic salts, and may be 
detected by their usual reactions. Thus iron albuminate is rapidly 
blackened by the presence of ammonium sulphide, because ferrous sul- 
phide is formed from it exactly as from any of the inorganic salts. On 
subjecting these albuminates to certain chemical manipulations, how- 
ever, the metal seems to become more firmly attached to the proteid, 
for ammonium sulphide acts on it much more slowly. The metal is 
then said to be masked, because its presence is not so readily detected 
as in ordinary combinations. Partially masked preparations have been 
formed artificially, but in the body the process is carried much further, 
for in many of their proteid compounds the metals cannot be detected 
by any of the ordinary tests, however long the reagents may remain 
in contact with them, and their presence is recognized only when the 
proteid is destroyed by heat or other similar agencies. 

When a solution of a metallic salt comes in contact with a living 
tissue, such as the mucous membrane of the mouth or stomach, the al- 
buminate is at once formed, and the acid with which the metal was 
combined is set free. The more completely dissociated the ions of the 
salt are, the more rapid is the reaction with proteid and the more in- 
tense the local action. Thus the more readily ionized inorganic salts 
act more strongly than the organic ones which are slowly dissociated, 
and these in turn are more liable to cause marked local changes than 
the double salts, which are dissociated with difficulty. 1 Other factors 
determining the nature of the local action are the character of the pre- 
cipitate and the activity of the acid formed, the latter again varying 
with the extent to which it is dissociated into ions ; it therefore exer- 
cises the same astringent or corrosive effects as if it had been applied 
uncombined, but its action may be modified by the presence of a layer 
of metallic albuminate protecting the surface. Thus when a weak solu- 
tion of lead acetate is applied to a mucous membrane, the metal forms 
an albuminate with the proteids lying on the surface and in the more 
superficial parts of the cells. This albuminate forms a continuous sheet 
over the mucous membrane, and the very dilute acetic acid formed is 
incapable of inducing any reaction. If a stronger solution be applied, 
however, the metallic precipitate extends more deeply into the cell, 
while the acetic acid, being more concentrated, exercises some irritant 
action. A- s *he concentration increases, the deeper parts of the epi- 
thelial cells are coagulated, and at the same time the acid becomes more 
destructive, so that eventually the superficial layer of the epithelium is 
killed and the deeper layers are attacked. The acetate of lead may 
thus act as an astringent, covering a mucous surface with a protective 
1 Paul. Bedeutung der Ionentheorie f. d. physiol. Chemie, 1901. 



THE HEAVY METALS. 627 

pellicle of insoluble albuminate, as an irritant, which induces an in- 
crease in the circulation of the part, a more rapid division of the cells 
and an effusion of liquid, or as a corrosive, involving the superficial 
layer of cells, and sometimes even the deeper ones in its destructive 
effects. 

When the nitrate of lead is applied, the astringent effect is much less 
evident, the irritant and corrosive more marked, because the salt is 
more readily dissociated and the reaction is therefore more rapid, and in 
addition the nitric acid is much more corrosive than acetic acid. The 
same metal attached to different acids may therefore induce very dif- 
ferent effects, in the one case acting chiefly as an astringent, in the 
other as an irritant and corrosive. 

The character of the precipitate formed also determines to some ex- 
tent the local action of the metallic salts. Thus the salts of mercury 
are more irritant and corrosive than those of the other metals, partly 
perhaps, because the precipitate is less continuous and more loose and 
flaky, partly because it is soluble in excess of proteid, and therefore 
allows the unattached molecules to penetrate deeply, while the lead 
albuminate remains on the surface of the membrane. The metals also 
differ in their toxicity, and a trace of mercury is sufficient to kill a 
cell, whereas a larger amount of lead may be absorbed by it without 
injury. 

In addition salts which have a very strong affinity for water with- 
draw fluid from the cells and thus act more strongly on them than 
others which have not this character ; for example dried alum is much 
more destructive to the tissues with which it comes in contact than 
alum containing its ordinary water of crystallization. 

The different metallic salts therefore vary in their local action 
within wide limits — from the formation of mildly astringent mem- 
branes to the production of widespread necrosis and destruction of tissue. 

The insoluble salts come into less intimate contact with the tissues, 
and have much less effect ; but many of them are slowly formed into 
albuminates and may then act as irritants or astringents. 

The most powerful corrosive salts of any metal are those which are 
most rapidly dissociated into ions, that is, the chlorides and nitrates, 
provided they are soluble. The sulphates are much less irritant, be- 
cause they are less readily dissociated, and perhaps because the sul- 
phuric acid may fail to penetrate the cells owing to its being less 
volatile and its anion having less permeating power than that of hy- 
drochloric or nitric acid. (See page 535.) The iodides and bromides 
are generally regarded as less irritant than the chlorides, but are less 
frequently used and less well known. 

The least corrosive of the salts of the metals are those formed with 
the slowly dissociated organic acids, such as the acetates, tartrates or 
citrates. When these are united with a metal which in itself is not a 
very active poison, such as lead, they are almost purely astringent. 
On the other hand, the acetate of silver or of mercury tends to be 
irritant and corrosive, from the poisonous action of these metals on the 



628 THE HEAVY METALS. 

tissues. In any case, the acetates are less irritant than the correspond- 
ing chlorides and nitrates, provided these are equally soluble. 

The local action also varies in the same salt of different metals. 
Lead is the most astringent of the metals ordinarily used in solution, 
while mercury salts have little or no astringent action, owing to their 
specific poisonous action on the cells. Iron and alum approach most 
nearly to lead, then copper, zinc and silver, and at a longer interval 
mercury. 

It is impossible to arrange the metallic salts as either astringents or 
irritants, because in every instance the eifect varies with the concen- 
tration, and with many other features, such as the condition of the 
surface to which they are applied, and the quantity of proteid with 
which they come in contact before they actually reach the living mem- 
brane. 

Of the salts in common use the most astringent are lead acetate and 
alum ; the most irritant are the perchloride and the nitrate of mercury, 
the chlorides of zinc, copper, tin and antimony, while the chlorides 
of iron, sulphates of copper, zinc, iron and manganese, the acetates 
of copper and zinc and the nitrates of silver and lead are astringents 
when applied in very dilute solution, but tend to irritate and corrode 
in larger quantities. In most cases the effects of the last group are 
made up of a mixture of astringent and irritant action. 

The insoluble preparations of mercury tend to irritate and corrode 
the surfaces to which they are applied, but the insoluble salts of the other 
metals are generally astringent. It is difficult to determine how far the 
so-called astringent and protective action of these insoluble substances 
is due to the formation of albuminates, and how far to their acting 
mechanically as protective coverings over irritated surfaces, but the 
latter factor is undoubtedly the more important in many instances. 

The precipitation induced by the astringents involves only the surface 
layer of cells, but the membrane formed protects the part from me- 
chanical and chemical irritation, and thus lessens congestion and inflam- 
mation. In addition several authors 1 have found that the astringent 
salts contract the vessels of the frog's mesentery by direct action on 
their coats, and have inferred that the same constriction is induced in 
the mucous membranes, when they are applied to them. Schiitz 2 
found that the 'secretion of the frog's skin and tongue is lessened 
when these parts are washed with astringent metallic salts, and it is 
quite possible that when these are applied to inflamed membranes, they 
may constrict the vessels and lessen the secretions, as well as form a 
protective membrane. When irritation is induced, the vessels of course 
dilate, and congestion and exudation follow. 

The local action is due to the formation of albuminate compounds 
and the liberation of acid. If the metal be applied in the form of an 
albuminate, this irritation is almost entirely absent except in so far as 

1 Bosenstirn, Eossbach's Pharmakologische Untersuchungen, ii., p. 84. Heinz, Vir- 
chow' s Arch. , cxvi. , p. 220. 

2 Arch. f. exp. Path. u. Pharm., xxvii., p. 202. 



THE HEAVY METALS. G29 

the poisonous action of the metal may cause necrosis and consequent 
irritation and inflammation. The double salts of the metals are also 
less liable to irritate, because they do not precipitate albumin, and 
their dissociation only occurs slowly and is not confined to the point 
of application. Of course if these double salts are decomposed by 
acids, as in the stomach, they may act as irritants. 

The salts of the heavy metals are often only slowly Absorbed. 
Mercury is again an exception, but even mercury does not induce gen- 
eral symptoms until many hours after its administration. The other 
metals given by the mouth pass through the alimentary canal for the 
most part unabsorbed. In recent years it has been disputed whether 
iron, manganese, copper and other metals are absorbed at all, but 
investigation with more accurate methods has shown that iron and 
manganese pass into the tissues from the alimentary tract, and it seems 
probable that a small proportion of most of the metals finds its way into 
the blood. At the same time there is no question that the great pro- 
portion of most of the metals passes through unabsorbed, and is devoid 
of any effect except from its local action. It is probable that the 
small quantity taken up by the stomach and intestine is first formed 
into proteid compounds in every instance, but there is very little 
known as to the process. When there is any lesion of the stomach and 
intestine, and particularly when the salt induces irritation and con- 
gestion itself, much more of the metal is taken up than by the normal 
epithelium. But even in the most favorable circumstances little of 
the metal is absorbed, and in acute poisoning the symptoms arise from 
the local irritation and corrosion, and only to a smaller extent from 
the general action of the metal. 

If the absorption of the metals is slow, their Excretion progresses 
even more gradually, and repeated administration leads to their accum- 
ulation in the tissues and thus to intoxication. The metal seems to 
leave the blood very rapidly, and to become stored up in various 
organs, chiefly the liver, to a less extent the spleen, kidney, and bone 
marrow. While some of the metal is deposited in the liver and other 
organs, another part is excreted, for the most part along the alimentary 
tract. Thus it is found in the saliva and gastric secretion, to a much 
larger amount generally in that of the lower parts of the small intes- 
tine, in the csecurn and in the large bowel. A comparatively small 
amount escapes with the urine. Some metals have been detected in 
very small quantity in the milk, and there is reason to suppose that 
traces are eliminated by the other cutaneous secretions. 

The General Action of the heavy metals in man is often elicited 
only by their prolonged ingestion, but it has been studied in animals 
by the intravenous or subcutaneous injection of the albuminates or of 
the double salts, which do not precipitate the proteids. The ordinary 
salts cannot be used, because the precipitated albumin of the blood 
causes embolism, and this obscures the symptoms. The symptoms of 
acute metallic poisoning elicited thus in animals generally resemble 
fairly closely those of chronic poisoning in man. Of course the ana- 



630 THE HEAVY METALS. 

tomical lesions induced in the latter by the constant presence of small 
quantities of metals in the nutritive fluids, can only be induced to a 
limited extent in such experiments. 

Even when the heavy metals are injected into the blood in consid- 
erable quantity, the symptoms are often late in appearing, in the case 
of aluminium only after several days, so that the slowness of the ab- 
sorption from the intestine is not the only explanation of the delay in 
the onset of the intoxication. 

The general symptoms of metallic poisoning, as distinguished from 
those due to the local action at the point of application, arise chiefly 
from the central nervous system, and from the excretory passages — 
the alimentary canal and the kidney. Metallic poisoning always in- 
duces disturbance of the Stomach and Intestine, manifested by loss of 
appetite, pain and discomfort in the abdomen, nausea, vomiting and 
purging. In some cases no lesion of the canal is observed post mortem, 
but in the great majority congestion and swelling of the mucous mem- 
branes of the stomach and intestine is seen, or the whole surface may 
be covered by a diphtheritic membrane composed of necrosed cells 
and inflammatory exudate. Beneath this haemorrhages occur, and if 
the animal live long enough, ulcers are formed, so that the whole con- 
dition can scarcely be distinguished from that of dysentery. Some 
metals act strongly on the mouth and salivary glands, salivation being 
one of the earliest features of mercury poisoning. The lining mem- 
brane of the mouth becomes congested and inflamed, and numerous 
shallow ulcers are formed in it. 

The heavy metals thus seem to have a specific action along the 
alimentary tract quite independent of the local action induced when 
they are swallowed. This is connected with their excretions along it, 
although it seems inadvisable in the present state of knowledge to say 
that they irritate the digestive tract because they are excreted in it. 
One or two metals, notably lead, cause constipation and colic when 
they are absorbed into the blood, but under certain circumstances they 
too induce purgation. 

Another organ which suffers from the circulation of metals in the 
blood is the Kidney. Comparatively little of the metal is excreted in 
the urine, but it is found that most of this class act as diuretics in small 
quantities. Somewhat larger doses irritate the renal epithelium, and 
albumin appears in the urine, along with casts and in severe cases 
blood cells and haemoglobin. If this irritation of the secretory cells 
be long continued, it sets up a secondary inflammation of the intersti- 
tial tissue, and cirrhosis of the kidney results. 

The Circulation is differently affected by different metals, or at any 
rate, the effects on the heart and vessels are described differently by 
the writers on the subject. Very often the heart is affected only in 
the last stages of poisoning, and it is impossible to determine how far 
its failure is due to direct action, and how far to the general disorder 
of the nutrition. The blood-pressure invariably falls towards the 
fatal issue of the intoxication, and as a general rule, a slow fall is 



THE HEAVY METALS. 631 

observed from the beginning. This fall in blood-pressure has been 
ascribed to the heart action, to depression of the vaso-motor centre, 
and to paralysis of the splanchnic terminations in the mesenteric ves- 
sels. It may doubtless be induced by different factors in the different 
forms of intoxication, but there is no question that it is partly due to 
the dilatation of the vessels of the intestines and stomach from the 
inflammation of these organs. 

Several metals have been found to lessen the alkalinity of the Blood 
by increasing the amount of lactic acid in it, but this does not seem 
a common feature in metallic poisoning. The general malnutrition 
from the gastro-intestinal action renders it impossible to determine 
whether the metals often alter the metabolism of the body through 
directly affecting the cells, but it is not improbable that this is the case, 
for the loss of weight is often too rapid to be explained by the starva- 
tion alone. 

The Central Nervous System is always affected more or less by the 
presence of the metals in the blood. As a general rule, the symptoms 
are a mixture of those of stimulation of certain divisions with those of 
paralysis of others. Several metals induce disturbance of the psychical 
centres, manifested in delirium, hallucinations and mania, or in stupor 
and coma. Convulsions of all forms indicate that the motor areas of 
the brain, the basal ganglia and the spinal cord are affected; thus 
epileptiform convulsions, chorea, clonic and tonic spasms occur from 
metallic poisoning. In several instances actual lesions of the brain 
cells have been shown to be caused by the ingestion of the metals. 
They often cause general weakness, or paresis of certain groups of 
muscles, and in addition to their specific action on the nervous centres, 
they may induce a peripheral neuritis (lead). The muscles do not 
seem to be so readily affected in general poisoning, although a solution 
of a non-irritating metallic salt generally paralyzes muscles suspended 
in it. 

Therapeutic Uses. — In therapeutics only mercury and iron are largely 
employed for their effects after absorption, while the others have a 
more or less extensive use for their local effects as astringents, irritants, 
caustics or styptics. Iron is not prescribed for its general action on the 
organs, but to supply the place of food-irons in the formation of he- 
moglobin. Mercury is used for its specific effect in syphilis, and some 
of its preparations have been advised as diuretics. Not infrequently 
the local action of the heavy metals is supposed to be induced after ab- 
sorption, and prescriptions are met with containing lead or iron which 
are intended to stay haemorrhage from the lungs or from the kidneys. 
It ought to be recognized, however, that lead or iron is absorbed only 
in minute quantities, and that they have no predilection for the bleed- 
ing points. If they were capable of coagulating the blood after ab- 
sorption, and thus stopping hemorrhage, they would certainly do so in 
the portal circulation and would not be carried to the lungs or kidney 
before they acted. As a matter of fact, however, they never reach the 
blood except in forms in which they have no astringent or styptic action. 



032 THE HEAVY METALS. 

Many of the metallic salts are powerful antiseptics, partly no doubt 
from their coagulating the proteids of the microbes, but also from a 
specific poisonous action on them, which is quite distinct from their 
precipitating action. As a general rule the antiseptic power varies 
with the amount of dissociation of the salt, that is, with the number of 
metallic ions present in the solutions, although the undissociated mole- 
cule also seems to have some influence, and a salt which is dissociated 
with difficulty may in some instances make up for this drawback by 
the more intense toxicity of the metal. 1 The most widely used metallic 
antiseptics are the mercurial salts, in particular the perchloride, but 
other metals have recently begun to play a more important role in sur- 
gery than heretofore. Almost incredibly small quantities of some of 
the metals have been found to be rapidly fatal to some of the algse, the 
bacteria, and the infusoria. Thus one part of the perchloride of mer- 
cury in one million parts of water kills spirogyra, one of the simpler 
alga?, and water distilled from copper vessels is rapidly destructive to 
it. Israel and Klingmann 2 hung small pieces of copper foil in water 
for a few hours, and then diluted this water a hundred times and found 
it still poisonous to many lower organisms. Silver was less active and 
lead still less so. The amount of copper in the original solution was 
too small to be recognized by any chemical test, much more so then in 
the further diluted portion. These results, which were first obtained 
by Naegeli, and which have been confirmed by other observers besides 
Israel and Klingmann, indicate that certain lower organisms are much 
more sensitive to the action of copper, and probably of other metals, 
than the more highly organized plants and animals. Further exami- 
nation of their effects as antiseptics in medicine and surgery is certainly 
desirable. Other curious effects on the growth of bacteria have been ob- 
served by Bolton and Brown, 3 who found that a piece of metal placed 
on a culture of microbes in gelatin causes curious alternating zones 
of intense growth and of sterility. These observations have recently 
been extended by Thiele and Wolff, 4 who state that silver, mercury and 
copper plates prevent the growth of microbes owing to minute traces 
of these metals being dissolved in the medium. Several other heavy 
metals — iron, lead, zinc, tin, gold, platinum and aluminum — proved 
devoid of action. Another explanation has been suggested by Novy 
and Freer, that these metals act by forming peroxides analogous to 
peroxide of hydrogen and the peracids (see page 592), and this view 
certainly appears more plausible than one that supposes a solution of 
copper to be toxic in such dilution as that tested by Israel and Kling- 
mann. A practical application of this bactericidal action of the metals 
has been made by the introduction of solutions of colloid forms of 
silver and mercury as antiseptics. 

1 Kronig u. Paul. Ztschr. f. Hygiene, xxv., p. 1. 
2 Virchow's Arch., cxlvii., p. 293. 

3 Transactions of the Assoc, of Amer. Physicians, xii., p. 488. 

4 Arch. f. Hygiene, xxxiv., p. 43. 



ANTIMONY. G33 



I. ANTIMONY. 



The preparations of antimony played a much more important role in 
therapeutics in the earlier part of last century than at the present time, 
and promise to be used to a still more limited extent in the future. 
In many respects they resemble arsenic in their effects, and may be 
looked upon as forming a link between it and the salts of the other 
heavy metals. The salt most commonly used is tartar emetic, or the 
double tartrate of antimony and potassium [K(SbO)C 4 H 4 O ] . The 
effects of this salt were at one time believed to be due in part to the 
potassium, but have been shown to be those of the antimony alone. 
Many other compounds of antimony have been used in therapeutics, 
and several others are still found in the pharmacopoeias, but they differ 
for most part from tartar emetic only in the rapidity of their action. 

Tartar enietic, like other double salts, is not corrosive, because it 
does not precipitate proteids except in acid solutions, in which it is 
decomposed into simpler forms. The chloride of antimony, on the 
other hand, readily dissociates the antimony ion and is a powerful 
caustic when applied to the skin or the mucous membranes. 

When rubbed on the Skin, however, tartar emetic causes redness, 
and a papular eruption, which later passes into vesicles and pustules. 
If the application be further persisted in, these pustules may become 
confluent and form small abscesses, and later cause extensive necrosis 
and ulceration of the skin. The points of origin of the papules are the 
openings of the cutaneous glands and the hair follicles. 

Symptoms. — Tartar emetic has a slight, acrid taste, and in very 
small quantities causes no symptoms, except some perspiration. In 
somewhat larger doses its ingestion is followed by nausea and vomiting, 
with very marked depression and the usual accompaniments of emesis, 
such as salivation, profuse perspiration and acceleration of the pulse 
(see Apomorphine, page 23-5). In antimonial poisoning the vomiting 
is violent and continuous, the ordinary contents of the stomach being 
first evacuated, and then a slimy mucous fluid, which may later con- 
tain blood. In some cases it is said that no gastric symptoms are 
observed, but these must be exceedingly rare. The vomiting is ac- 
companied by profuse w T atery diarrhoea, resembling that of arsenical 
poisoning, and by great muscular weakness and collapse. The pulse 
may be somewhat accelerated at first, but is weak, and later becomes 
slow and irregular. The skin is cold and covered with a clammy per- 
spiration, and cyanosis of the face and extremities is generally marked. 
The respiration is slow and may be irregular, the voice weak and 
husky, the temperature is depressed, and the patient falls into a coma- 
tose condition, which deepens, until after a few weak convulsive move- 
ments the respiration ceases. The urine is sometimes increased in the 
beginning of the poisoning, but later may become scanty or entirely 
suppressed. It often contains albumin. 

The minimum fatal dose of tartar emetic is doubtful, as the greater 
part of the poison is generally removed by vomiting. Recovery has 



634 THE HE A VY METALS. 

been observed after very large quantities, while in other cases 0.1 (j. 
(2 grs.) has proved fatal. 

Chronic antimonial poisoning is very rare and difficult to diagnose. The 
symptoms are depression, headache, giddiness and confusion, drowsiness and 
indistinct sight. The appetite is bad, and the patient complains of heavi- 
ness, discomfort, or pain in the region of the stomach, general weakness and 
exhaustion. Profuse diarrhoea may be present, rapid loss of flesh, albumi- 
nuria and finally collapse. Pustular eruptions have been observed from the 
prolonged internal use of tartar emetic. 

Action. — Many of the symptoms of antimonial poisoning, the pro- 
fuse perspiration, salivation and, to some extent at least, the collapse, 
are manifestly secondary to the Emetic Action, and the cause of the 
vomiting has, accordingly, been repeatedly investigated. It may be 
stated at once that some authors attribute the vomiting to a central 
action, but that the majority are inclined to regard it as mainly due to 
irritation of the stomach. Large doses of antimony affect the stomach 
and bowel in the same way as arsenic, inducing hyperemia and swell- 
ing and loosening of the epithelium, but smaller quantities such as are 
used in therapeutics do not seem to cause any obvious lesion, It is 
found that tartar emetic injected hypodermically or intravenously 
causes nausea and vomiting, but much larger quantities are required 
than are requisite when the drug is given by the mouth. This indi- 
cates a direct action on the stomach, rather than on the centre for 
vomiting, and this view is supported by the fact that antimony is 
found in the stomach and intestine when it is injected intravenously. 
The obvious explanation would therefore seem to be that antimony 
given by the mouth acts as a gastric irritant, and causes vomiting, 
while when it is injected intravenously it is carried to the stomach, 
and again causes irritation with the same result. The whole of the 
antimony swallowed acts at once on the stomach, while only a part 
of that injected exerts its action on it, and larger doses are therefore 
necessary when the poison is administered in the latter way. 

This explanation is opposed, however, to an observation made by Orfila, 
who found that when the stomach was excised and replaced by a dead blad- 
der, tartar emetic still caused the movements of vomiting, which even 
expressed the fluid in the bladder. Of course no antimony could be excreted 
into the bladder, and no irritation or reflexes could arise from it. Again 
Mosso states that when the vagus nerves are cut below the diaphragm, tar- 
tar emetic fails to cause vomiting when it is swallowed, but large doses have 
their usual effect when injected into a vein. These observations appear at 
first sight to indicate that tartar emetic acts centrally, but it has been sug- 
gested that although the poison could not act on the stomach in Orfila's 
experiment it might cause vomiting by causing irritation of some other part 
of the alimentary tract. As regards Mosso' s results, the relation of the 
vagus nerve to vomiting is still so obscure that it is dangerous to draw any 
inference from such experiments. On the whole the evidence goes to show 
that the emesis is due to irritation of the gastric mucous membrane by the 
antimony. 

The action of tartar emetic on the Stomach has been explained by 
supposing that the acid gastric juice decomposes the double salt and 



ANTIMONY. 635 

that the chloride thus formed acts as a corrosive in the same way as 
the chlorides of the other heavy metals. This, however, fails to ex- 
plain the fact that the same effects are met with in the intestine, in 
which no such acid fluid exists, and that vomiting is induced readilv 
when the gastric juice is neutral in reaction (Mosso). A more prob- 
able explanation is that antimony has a specific irritant effect on the 
mucous membranes of the stomach and bowel, similar to that of ar- 
senic. The irritation is greater, however, and is induced more rapidly, 
so that vomiting is caused much more easily. At the same time, an- 
timony is more slowly absorbed than arsenic, so that its action re- 
mains confined to the stomach, and as the vomiting removes much the 
greater part of the poison, the intestine remains unharmed except 
when large quantities have been swallowed and the emesis is from anv 
cause insufficient. In chronic poisoning ulceration of the small intes- 
tine is said to occur, especially around the solitary follicles and Pey- 
er*s patches. 

The acceleration of the Pulse seen after tartar emetic is due for the most 
part to the emetic action and not to the absorption of the drug. When in- 
jected into a vein in animals, antimony causes a slow and weak pulse, 
although this is preceded in some cases by slight acceleration. The action 
is a direct one on the cardiac muscle, as may be seen by perfusing an excised 
frog's heart with blood containing some tartar emetic. The cardiac nerves 
do not seem to be affected. 

The Blood-pressure falls throughout the experiment, partly owing to the 
weakness of the heart but chiefly owing to an action on the vascular mecha- 
nism similar to that described under arsenic. Here again it is doubtful 
whether the effect is due to the vaso-motor centre or to the peripheral nerves 
and muscle of the vessels, but the latter are certainly involved, for stimula- 
tion of the spinal cord fails to contract the mesenteric vessels. 

The Respiration is often slightly accelerated at first, and may be shallow 
and irregular from the nausea ; but in cases of poisoning it becomes slow and 
labored, and eventually ceases along with the heart. The respiratory centre 
is perhaps affected directly to some extent, but the changes in the breathing 
are probably due for the most part to the disturbance of the circulation, and 
to the action on the alimentary canal. The statement made by some of the 
older writers that antimony caused hepatization of the lungs, has been shown 
to be incorrect. 

The Central Nervous System is depressed by antimony in the frog, 
spontaneous movements persisting after the reflexes have disappeared, 
according to some authors. This has been interpreted to mean that antimony 
paralyzes the sensory part of the cord or its connection with the motor cell, 
while leaving the connections between the latter and the brain intact ; but 
the statement itself requires farther confirmation. The paralysis is due to 
the direct action of antimony on the nerve cells and not to the disordered 
circulation, for frogs poisoned with antimony are paralyzed sooner than 
others in which the circulation is entirely destroyed by the excision of the 
heart. The effect of antimony on the central nervous system of the mammals 
is more obscure, for it is impossible to ascertain how far the changes are due 
to direct action and how far they are attributable to the disturbance of the 
circulation and the alimentary canal. There is reason to believe, however, 
that the poison depresses to some extent the nerve cells here also. Accord- 
ing to Schaffer, the cells of the spinal cord undergo a degeneration marked 
by the disappearance of the chromatin in chronic antimonial poisoning. 

The Depression and Collapse of antimony poisoning are caused by 1 1 1 • - 



036 THE HEAVY METALS. 

gastric effects and the slowed circulation acting on the central nervous sys- 
tem, and not, as is sometimes stated, to the peripheral nerves and muscles 
being affected. The voluntary muscular tissue is undoubtedly weakened to 
some extent in the frog, but only after large doses and at a late stage. The 
muscles then contract somewhat more weakly than normally, and are more 
readily fatigued. 

Many of the Secretions are increased by tartar emetic, such as the peri 
spiration, the saliva and the mucous secretion of the respiratory tract. This 
is not due to any direct action on the glands, for the same effect is induced 
by anything which causes vomiting. (See Apomorphine, page 235.) The 
urine is sometimes increased by antimony, at other times it is diminished or 
suppressed. This is perhaps due to a preliminary stimulation of the renal 
epithelium, which passes into acute irritation when much of the drug is ab- 
sorbed. The action on the urinary secretion is not very marked, however. 

The irritant action of tartar emetic on the Skin when it is applied 
to it in ointment, has been explained by the double salt being broken 
up by the acid formed in the decomposing secretions, and an analogy 
has been drawn between it and the irritant effects in the stomach. In 
support of this it is said that the addition of alkalies to the tartar 
emetic ointment prevents the formation of pustules. This does not 
seem a very happy explanation, although it accounts for the formation 
of pustules at the openings of the skin glands. The double salts of 
other metals, however, which would form irritants in the same way as 
tartar emetic have no special effect on the mouths of the gland ducts. 
Nunn finds a specific effect on the skin of the frog when tartar emetic 
is injected, similar to that induced by arsenic, but more rapid in its 
onset, and this may explain the pustulant action. A pustular erup- 
tion is said to be induced in some cases when antimony is taken 
internally. Pustules also occur in the oesophagus when tartar emetic 
is swallowed, and irritation of the mouth and swelling of the lips 
have been observed. 

The effects of antimony on the Nutrition have not been so carefully 
examined as those of arsenic, but, as far as is known, present a strong re- 
semblance to them. Thus fatty degeneration of many organs is induced by 
its prolonged use, the nitrogen of the urine is found to be increased, and the 
glycogen disappears from the liver. Very small quantities of antimony 
given repeatedly are said to increase the glycogen and fat of the liver, with- 
out apparently altering the nitrogen of the urine. 

The fall in Temperature after antimony is often very considerable, amount- 
ing in animals to 6° C. in the course of a few hours. It is explained by the 
slowness of the circulation and by the general depression and collapse and 
profuse perspiration. 

Antimony is Absorbed from the skin very slowly, and from the stomach 
and intestine. It passes into the tissues much more gradually than arsenic, 
however, and its action on the stomach, can, therefore, be elicited without 
danger of its causing general symptoms. After absorption antimony is 
found in considerable quantity in the liver, which stores it up for some 
time. It is excreted into the stomach and intestine, in the urine, and, it is 
said, in the bile and milk. 

The Chloride of Antimony (SbCl 3 ) differs from tartar emetic chiefly in being 
a violent corrosive, which combines to form albuminates and thus acts like 
the other salts of the heavy metals, and also tends to withdraw fluid from 
the superficial tissues, when it is applied in a concentrated solution. The 



ANTIMONY. 637 

other compounds of antimony act like the double tartrate except that most of 
them are much slower in their effects. Stibine or antimonuretted hydrogen 
(SbH 3 ) differs entirely from arsine (AsH 3 ) in its effects which are similar to 
those of the other antimony preparations. It is only feebly toxic, and owes 
its activity to its being decomposed in the organism. 

Preparations. 

Antimonii et Potassii Tartras (U. S. P.), Antimonium Tartaratum 
(B. P.), tartar emetic, tartarated antimony ((KSbOC 4 H 4 6 ) 2 + H 2 0) forms 
colorless, transparent crystals, or a white granulated powder, without odor, 
and having a sweet, afterwards disagreeable, metallic taste, soluble in 17 
parts of cold water, insoluble in alcohol. Dose as a diaphoretic 0.002-0.008 
G. (sV-j gr.), as an emetic 0.03-0.1 G. (J-2 gr.). 

Vinum Antimonii (U. S. P.), Vinum Antimoniale (B. P.), 4 parts of 
tartar emetic in one thousand (U. S. P.), in 875 parts (B. P.). 0.6-2 c.c. 
(10-30 mins.), diaphoretic ; 4-15 c.c. (1-4 drs.), emetic. 

Tartar emetic is also contained in the compound syrup of squills U. S. P. 

Antimonii Oxidum (IT. S. P., B. P.) (Sb 2 3 ), a heavy, gray, insoluble and 
tasteless powder. 0.05-0.1 G. (1-2 grs.). 

Pulvis Antimonialis (U. S. P., B. P.), James' powder, consists of antimony 
oxide 1 part to 2 parts of phosphate of calcium. 0.15-0.3 G. (3-6 grs.). 

Antimonii Sulphidum (U. S. P.) (Sb 2 S 3 ). 

Antimonii Sulphidum Purification (U. S. P.), Antimonium Nigrum Purifi- 
catum (B. P.) (Sb 2 S 3 ), a heavy grayish black powder, odorless, tasteless and 
insoluble in water. 0.015-0.06 G. (f-1 gr.). 

Antimonium Sulphuratum (U. S. P., B. P.), Kermes mineral, consists of 
antimony sulphide (SbS 3 ) with a small amount of oxide (Sb 2 3 ) — an amor- 
phous, reddish brown powder, odorless, tasteless and insoluble in water. 
0.06-0.3 G. (1-5 grs.). 

Pilulx Antimonii Composite (U. S. P.), Plummer's Pills, each contain 0.04 
G. (f gr.) of sulphurated antimony and an equal amount of calomel. 1-2 
pills. 

Pilula Hydrargyri Subchloridi Composita (B. P.), Plummer's Pills, compound 
calomel pill, 8 grains contain nearly 2 grains each of calomel and of sul- 
phurated antimony. 4-8 grs. 

Therapeutic Uses. — Antimony is used to a much less extent in med- 
icine than was formerly the case. In the seventeenth century it was 
prescribed so widely and was believed to do so much harm, that the 
graduates in medicine of Heidelberg were required to take an oath 
never to use it. At present it is used to a limited extent as an emetic, 
but is slow in action and induces greater depression and more pro- 
longed nausea than the other drugs which are prescribed for this pur- 
pose, such as apomorphine, ipecacuanha, or sulphate of copper. It is 
therefore seldom used to evacuate the stomach in cases of poisoning or 
of foreign bodies in the stomach or oesophagus. Its expectorant action 
is taken advantage of in acute bronchitis in which the secretion of the 
bronchial mucous membrane is insufficient, but it is of less value when 
the secretion is abundant. In commencing bronchitis tartar emetic is 
sometimes given until vomiting occurs, and then continued in smaller 
doses and at longer intervals. 

It is also used as a diaphoretic to some extent, in the same doses as are 
prescribed as expectorants, but it has been almost entirely supplanted by 
pilocarpine for this purpose. James' powder was especially popular Bfi a 
diaphoretic, but is now seldom employed. 



638 THE HEAVY METALS. 

In acute fever antimony was formerly largely used as a depressant, more 
especially when delirium was a marked feature. The object was to produce 
a mild collapse, but the treatment has been entirely abandoned by most 
authorities, and probably did more harm than good. Acute lobar pneu- 
monia was almost universally treated by tartar emetic at one time, and an 
attempt has recently been made to revive this treatment, but without suc- 
cess. 

Antimony has been advised instead of arsenic in the internal treatment of 
skin disease, but it is impossible to state at present how far it is capable of 
replacing the more widely used drug. 

In all cases in which there is marked depression or weakness, in which 
the stomach or bowel is disordered, or in which the circulation is feeble, the 
preparations of antimony are contraindicated. 

Tartar emetic w r as formerly used in ointment (one part to four) as a skin 
irritant, but its continued application has led in several cases to diffuse sub- 
cutaneous abscess, and sometimes to necrosis of bone, so that the tartar 
emetic ointment has passed into desuetude. 

In cases of Antimonial Poisoning, emetics are seldom required, but 
the stomach may be washed out by means of the stomach tube, if 
vomiting is not present, and a purge may be given to remove the poison 
in the bowel. Tannic acid is used to precipitate the antimony in the 
stomach, and the tannate formed must be washed out. A form of tan- 
nic acid which is usually available in emergencies is strong tea, which 
is also useful as a stimulant for the collapse. Lime or magnesia may 
be used to precipitate the antimony instead of tannic acid. 

Bibliography. 

Ackermann. Yirchow's Arch., xxv., p. 531. 
Badziejeiuski. Arch. f. Anat. u. Phys., 1871, p. 472. 
Saikowtiki. Yirchow's Arch., xxxiv., p. 73. 
Solovceitschyk. Arch. f. exp. Path. u. Pharm., xii., p. 438. 
Robert. Ibid., xv., p. 36. 
Grimm. Pfliiger's Arch., iv., p. 205. 
Harnack. Munch, med. Woch., 1892, p. 179. 
Ringer and Murrell. Journ. of Physiol., i., p. 241. 
Nunn. Ibid., i., p. 247. 
Thumas. Yirchow's Arch., cxxiii., p. 66. 
Mosso. Schmidt's Jahrbuch, clxix., p. 236. 

Chittenden and Blake. Studies from the Lab. of Physiolog. Chem. Sheffield Scientific 
School, ii., p. 87; hi., p. 106. 

Kubeler. Arch. f. exp. Path. u. Pharm., xxvii., p. 451. 

II. MERCURY. 

Mercury, one of the most powerful inorganic poisons, has been used 
in medicine for a loug time and in a large variety of forms. Some 
differences are observed in the action of these, but all of them induce 
the same general results, the differences existing only in their local 
effects, and being due to the salts differing in solubility and dissocia- 
bility. A soluble salt, such as the perchloride, comes into more inti- 
mate contact with the tissues, and therefore acts more powerfully 
locally, and is also absorbed more rapidly and in larger amount than 
calomel, which is entirely insoluble in water. Both the local and the 
general effects of the perchloride are more marked than those of calo- 



MERCURY. 639 

mel, therefore, but when sufficient mercury in the form of calomel is 
absorbed into the tissues, the general effects are the same as if an equal 
quantity had been taken up as perchloride. 

Mercury is absorbed and circulates in the blood in the form of the 
albuminate, which is insoluble in water, but is rendered soluble by ex- 
cess of proteid, and also by chloride of sodium in such quantities as 
are met with in the tissues. The solubility of the albuminate ex- 
plains how mercury is absorbed so much more quickly than any of the 
other heavy metals, and at the same time it may account in part for its 
greater corrosive action. The corrosion is due to some extent to the 
acid constituent of the preparation, but this is not greater than that of 
an equally soluble and equally dissociable combination of the acid with 
another metal. The mercurial ion itself is also corrosive, and its de- 
structive action is the more powerful because the precipitate formed with 
proteids is less insoluble in the surrounding fluids of the body and is 
therefore more flocculent and affords less protection to the surface, 
than those formed by the other heavy metals. The mercurial action is 
consequently not limited to the surface of a tissue but extends into the 
deeper cells. The highly corrosive action of the mercury ion has been 
ascribed to its great affinity for the amido-compounds which are con- 
tained in the albumin molecule. Liebermann has also shown that it 
has a special affinity for lecithalbumin, and it is possible that this may 
play an important role both in the absorption and in the slow excretion 
of the metal. 

The albuminate is formed rapidly when such soluble salts as the 
perchloride come in contact with the tissues, and the local corrosion is 
greater and the absorption more rapid than when an insoluble salt is 
ingested. A good deal of dispute has arisen as to the absorption of the 
insoluble salts of mercury, and it is frequently stated that calomel is 
first changed to the perchloride by the action of the hydrochloric acid 
of the stomach and by the chlorides of the tissues, and that only then 
is the albuminate formed. There is, however, no sufficient evidence 
that the perchloride is formed from the chloride, and such a change is 
not necessary to explain its absorption, for the proteids of the tissues 
can act on calomel as such, and, forming the soluble albuminate, allow 
it to be absorbed. It has been asserted of late that when calomel is 
injected hypodermically, the leucocytes take it up and carry it off as 
they do any other foreign insoluble body, and it is quite possible that 
they may take it up in the same way from the alimentary canal. At 
the same time the quantity of calomel which comes into intimate con- 
tact with the tissues is much smaller than in the case of the soluble 
perchloride, and a smaller proportion of calomel is absorbed therefore. 
In the same way other insoluble preparations of mercury are absorbed 
in the form of albuminates, and even the metal may be oxidized and 
absorbed when it is applied to the living surfaces or injected into the 
blood in a state of fine division. Thus the inhalation of mercury vapor 
by the lungs leads to general poisoning, often of a very malignant type, 
and mercury rubbed into very fine globules, and applied in ointment 



640 THE HEAVY METALS. 

to the skin, passes into the gland ducts and along the roots of the hairs, 
and, after being oxidized, is dissolved and absorbed into the tissues, in 
which it causes the typical mercurial effects. 

Symptoms. — Acute Mercurial Poisoning occurs only from the use of 
soluble preparations, and in particular from the perchloride of mercury 
or corrosive sublimate. Many cases have arisen from this poison being 
swallowed accidentally or with suicidal intent, but of late years an 
almost equal number has arisen from the perchloride being used as an 
antiseptic wash for large cavities. When corrosive sublimate is swal- 
lowed in poisonous quantity, the patient complains at once of the harsh, 
metallic taste, which is followed by burning pain in the mouth, throat 
and stomach. Nausea and vomiting set in very soon, and the vomited 
matter may contain shreds of mucous membrane and blood. Diar- 
rhoea and violent tenesmus, with watery or bloody stools, often con- 
taining shreds of membrane, may be among the early symptoms, or 
may only occur after twenty-four hours. These symptoms from the 
alimentary canal are accompanied by collapse, with a small, thready, 
sometimes irregular pulse, shallow, irregular, rapid respiration, cold, 
clammy skin, pinched features, and sunken eyes. The temperature is 
often subnormal, but sometimes fever is observed, although this is 
attributed by many to concurrent disease. The consciousness is usually 
unaifected, but in some cases somnolence, giddiness, or more rarely 
anxiety and restlessness have been observed. The urine is much 
diminished and complete anuria often occurs in a few hours. If the 
urine is not completely suppressed, it generally contains albumin, renal 
epithelium, casts, and more rarely sugar. Death may occur within an 
hour from shock, but more frequently the patient survives several days 
or even one or two weeks, the symptoms of intestinal corrosion and of 
renal irritation continuing, until he finally sinks from exhaustion. 

When acute poisoning occurs from the absorption of corrosive subli- 
mate from wounds, the symptoms of corrosion of the mouth and stomach 
are absent at first, but the dysenteric symptoms and the renal inflam- 
mation are produced in the same way as when the poison is swallowed. 
Here again the patient may die within a few hours, but more fre- 
quently survives for several days, and in the latter case the symptoms 
towards the end partake of the character of chronic poisoning. In 
particular, salivation and stomatitis set in in the course of a few days. 
These also occur when the poison is swallowed, although they are more 
liable to be overlooked, from the cauterization produced in the mouth 
by the local action. 

Chronic Poisoning. — A much more frequently observed form of 
poisoning is that induced by the prolonged medicinal use of mercury. 
It may arise from any of the preparations, and from any form of ap- 
plication, although some methods of administration are credited with 
being less liable to induce it than others. Thus inunction with mer- 
curial ointment and the use of calomel internally are both more liable 
to cause the severer forms of stomatitis than is corrosive sublimate. 
A single hypodermic injection of an insoluble preparation may induce 



MERCURY. 6il 

it in susceptible persons, because the mercury is only slowly absorbed, 
and passes into the tissues as gradually as if it were given by the mouth 
regularly for several days. This chronic poisoning or Mercurialism is 
due, not to the local action, but to the effects of the drug after absorp- 
tion. It is much more liable to occur in certain people than in others, 
but may follow the abuse of mercury in any case, and the cause of the 
abnormal susceptibility to mercury is unknown. When mercurialism 
begins to be manifested, the drug ought to be stopped, or the dose 
much reduced, until the symptoms disappear. Formerly it was be- 
lieved that the earlier symptoms of mercurial poisoning had to be in- 
duced in the cure of syphilis, but in modern therapeutics every effort 
is made to avoid them. The first symptoms generally arise from the 
mouth and throat, the patient complaining of a metallic taste, and of a 
feeling of numbness or soreness of the tongue and gums. The breath 
has an unpleasant foetid odor, the tongue is swollen and thickly coated, 
the gums are soft, swollen and often of a dark bluish-red or gray 
color and the flow of saliva is augmented. If the medication be 
continued as was often done formerly, ulcers appear on the gums 
and on the sides of the tongue where it comes in contact with the 
teeth, especially if these are carious, and on the mucous membrane of 
the cheeks ; the salivation increases and irritates the lips and the skin 
where it is exposed to the secretion. If the administration of mercury 
be still persisted in, the teeth become loose and fall out, gangrene of the 
gums, lips and throat, and necrosis of part or even of the whole jaw 
may follow, and may prove fatal by exhaustion and inanition due to 
the difficulty in swallowing and to the complete absence of desire for 
food. The milder forms of stomatitis and salivation are observed in a 
large proportion of cases of syphilis treated with mercury, according 
to some authors in 30 per cent, or more. It may be avoided, to some 
extent, at least, by scrupulous cleanliness of the mouth and teeth, by 
the filling of carious teeth, and by using a 2—4 per cent, solution of 
chlorate of potash as a mouth wash. 

The stomach and intestine also suffer in chronic mercury poisoning. 
The patient often complains of loss of appetite, and occasionally of a 
feeling of weight and discomfort in the stomach, nausea and vomiting, 
general weakness and loss of flesh. Colic and diarrhoea are frequently 
observed, or diarrhoea and constipation may alternate. These symp- 
toms are naturally more liable to occur from the administration of 
mercury by the mouth than by other channels, as here the action after 
absorption is reinforced by the direct local effects. Some fever is 
sometimes noted, but this is secondary to the affection of the mouth, 
bowel or skin, and is not directly attributable to the mercury. 

Occasionally skin eruptions are seen when mercury is given by the 
mouth, but much more frequently when it is applied to the skin. In 
the latter case they are not limited to the point of application, although 
they often begin from it and spread over a large surface 1 of the body. 
They are said to occur often without any other symptom of poisoning, 
except the fever and discomfort which they indue** themselves. They 
41 



642 THE HEAVY METALS. 

vary greatly in form, consisting of small reddish spots, large red ery- 
thematous surfaces, urticaria, or eczema, each of these occurring alone 
or in succession, and being usually followed by desquamation. The 
eruption generally lasts only 1-3 weeks, but in some cases has not en- 
tirely disappeared until three months after its first appearance, and in 
others has returned repeatedly afterwards. It is said to have been 
induced occasionally by a single dose of calomel. 

The urine is often somewhat increased, but may be decreased after- 
wards, and it not infrequently contains albumin, although the proportion 
of cases in which this occurs is much disputed, and the amount in the urine 
is generally very small. Glycosuria is much rarer in man, but has been 
frequently observed in rabbits after prolonged treatment with mercury. 

It is still a matter of doubt how far the sexual organs are involved 
in mercury poisoning. According to some authorities disturbances of 
the menstruation and even complete amenorrhcea have been observed, 
and abortion is also stated to have been caused by it. 

A general condition of cachexia may be induced by the presence of 
these disorders, and is marked by pallor, anaemia, emaciation, weak- 
ness and restlessness, with a tendency to fainting and disturbed sleep. 
The pulse is small, weak and quick, sometimes irregular, and the pa- 
tient often complains of breathlessness. 

Affections of the central nervous system are rarely induced now by 
the abuse of mercury in therapeutics, but are mentioned by some of 
the earlier writers, and still occur in the case of workers in mercury 
mines, in mirror, barometer and thermometer factories, and in other 
manufactories in which mercury is used and its fumes are inhaled by 
the workmen for prolonged periods. One of these affections is the 
mercurial erethism, a condition of abnormal irritability, timidity or 
shyness, accompanied by great muscular weakness, and sometimes 
developing into sleeplessness, delirium and transitory hallucinations. 
Another well-known form is the mercurial tremor, which affects the 
hands and arms first, later the legs, and sometimes extends over all the 
muscles of the body. Shooting pains along the nerves or in the joints 
are sometimes complained of, circumscribed areas of partial anaesthe- 
sia, amblyopia, anosmia or deafness have been described, and in some 
cases localized paralysis of the muscles of the arm or leg have been 
induced. These last differ from the paralysis of lead or arsenic poi- 
soning in the fact that no wasting of the muscles is observed, and the 
electrical reaction remains normal. According to Letulle they are due 
to the destruction of the myeline sheath of the peripheral nerves, the 
axis cylinder remaining intact. 

The symptoms of mercurial poisoning, both acute and chronic, in 
animals, resemble those in man so closely that it is unnecessary to de- 
scribe them further. 

Action — Lower Forms of Life. — The action of mercury on proteids 
extends to all forms of living matter. Whenever the metal comes into 
intimate contact with albumins, it forms the albuminate and destroys 
life. This poisonous action is naturally much more evident when solu- 



MERCURY. £43 

ble preparations are used than when the oxides or calomel are in ques- 
tion. Thus corrosive sublimate in a solution of one part in 50,000 
destroys infusoria in some 20 minutes, and even one part in one mil- 
lion kills algse in the course of a few days. The bacteria are some- 
what more resistant than these forms, but corrosive sublimate is said 
to delay the development of some of these, in a solution of one part in 
one million, and the anthrax bacillus fails to grow in blood which con- 
tains one part in 8,000. A solution of one part in one thousand is 
generally regarded as capable of disinfecting fluids completely in the 
course of a few hours, but there is no question that the germicidal 
power of corrosive sublimate has been much overestimated. Thus 
Geppert found that the spores of anthrax could be exposed to the ac- 
tion of a one per cent, solution for many hours and still develop as 
soon as the mercury was entirely removed. There is no doubt, how- 
ever, that corrosive sublimate and the other soluble salts of mercury 
ire among the most powerful antiseptics at present available. The 
insoluble preparations are less poisonous, owing to the difficulty in 
bringing them into intimate contact with the microbes, but calomel 
lias been shown to have some effect as an intestinal antiseptic. 

In the Higher Animals and in Man the same destructive effects are 
induced by the mercury preparations. The corrosion of the mouth, 
throat and stomach when the perchloride is swallowed, has already 
been mentioned. When it is applied to the other mucous membranes, 
similar effects are obtained, and when it is injected hypodermically, 
even in dilute solution, it induces intense pain, swelling and inflam- 
mation, which is rarely followed by suppuration, but which may 
result in the formation of cicatrices. Stronger solutions injected into 
animals often cause the formation of cheesy abscesses, and even dry 
necrosis of the skin and underlying tissue. The hypodermic or in- 
tramuscular injection of insoluble preparations is more liable to cause 
abscess formation, because the mercury is slowly absorbed and has 
therefore more time to induce its irritant effects. 

When solutions of corrosive sublimate are applied to the skin, they 
cause a feeling of numbness very often ; but when very strong solu- 
tions come in contact with tender parts of the skin, and in particular, 
when the salt itself is allowed to lie in contact with it for any length 
of time, deep corrosion, necrosis and sloughing may follow. Even the 
insoluble preparations are liable to set up irritation when they are 
rubbed into the skin, especially if there is any pre-existing tendency 
to cutaneous eruption. 

After absorption, mercury acts more especially on the alimentary 
tract and on the kidneys, although other organs are not exempt from 
its effects. 

The Salivation and Stomatitis, which are so frequently seen under 
mercurial medication, are obviously not due to the local action of the 
drug on its way to the stomach, for they occur equally readily when it 
is applied by hypodermic injection or by inunction. The salivation is 
apparently due to the direct action of the mercury on the Becretory 



644 THE HEAVY METALS. 

apparatus, for it often appears before any other symptom and is cer- 
tainly not the reflex effect of the irritation of the mouth. The saliva 
is sometimes excreted in enormous amounts, many litres of it being 
poured out in the course of twenty-four hours. It contains mercury, 
and has therefore a metallic taste, and tends to irritate the lips and 
skin where it comes in contact with them. In extreme cases it leads 
to sleeplessness from its accumulating in the back of the throat and 
awakening the patient with a feeling of suffocation. The stomati- 
tis is likewise due to the excretion of mercury by the saliva and by 
the other mucous secretions of the mouth and throat. The irritation 
caused by the metal leads to excoriations, and these to the formation 
of ulcers, particularly where microbes are present in large numbers, as 
around carious teeth. The necrosis of the jaws is due to these ulcers, 
penetrating to the bone and setting up periostitis, for mercury in itself 
has no specific action on the bone such as has been mentioned under 
phosphorus. 

Mercury has less direct effect on the Stomach, though congestion and 
even small haemorrhages in cases of poisoning indicate that it is not 
entirely immune ; the loss of appetite and malnutrition in chronic 
poisoning are ascribed to the presence of mercury in the saliva rather 
than to its affecting the gastric functions directly. In the Intestine, on 
the other hand, mercury is apparently excreted in large amount, and 
induces very distinct lesions. The parts affected are the caecum and 
colon, while the small intestine very often escapes almost entirely. 
The action of mercury is evidenced by hyperemia, redness and swell- 
ing of the mucous membrane, which later develop into necrotic sur- 
faces and ulcers along the folds ; these lend it an appearance almost 
indistinguishable from that of chronic dysentery and may eventually 
end in perforation. The symptoms from the intestine are in accord- 
ance with the lesions, consisting in constant purging with very fluid, 
sometimes rice-water stools, intense pain and tenesmus, blood and frag- 
ments of mucous membrane in the faeces. 

Small doses of mercurials given by the mouth act as Purges, causing 
soft stools generally without pain or straining. The insoluble prepa- 
rations are used for this purpose, as they act least on the stomach, and 
the mercurial purges par excellence are calomel and the metallic prep- 
arations — blue pill and gray powder. This effect is apparently due to 
their acting as intestinal irritants from their specific action on the in- 
testine. They apparently do not remain long enough in the stomach 
to be dissolved, and besides seem to have less tendency to induce irri- 
tation here. In the intestine, on the other hand, their longer sojourn 
and special affinity for the epithelium, leads to their partial solution 
and to their irritant action being developed. A small proportion of 
these insoluble preparations is absorbed from the intestine, but the 
great mass is thrown out unchanged in the stools, and thus very large 
doses of calomel sometimes induce no serious symptoms. Mercury acts 
in the intestine even when the bile is suppressed, and the stools are 
often of a greenish color, which has been ascribed to a metallic com- 



MERCURY. 045 

pound formed in the bowel, but which is really due to bile pigment. 
This is ordinarily decomposed by the microbes in the intestine with 
the formation of the faecal pigment, but mercury from its antiseptic 
properties prevents the growth of the microbes, and the bile therefore 
appears in the stools undecomposed and possessed of its ordinary 
color. » 

The mercurial purges, and in particular calomel, have often been 
credited with increasing the secretion of the Bile, but this has been 
shown to be incorrect, for Stadelmann {\n animals) and Pfaff (in man) 
found that the mercurial preparations had no effect on the secretion 
escaping from a biliary fistula. The belief probably arose from the 
green color of the stools, but this, as already mentioned, is due, not to 
the increase of the bile, but to its being preserved from putrefaction 
in the intestine. There is, in fact, no sufficient experimental or clini- 
cal evidence that the liver is in any way affected directly by mercury. 
The " biliousness " which is so often relieved by calomel or blue pill, 
is due, not to the liver, but to disorder of the alimentary tract. 

Mercury has no such powerful effect on the Unorganized ferments of 
digestion as it has upon the microbes, for though large amounts of the 
soluble preparations precipitate the pepsin in artificial digestion experi- 
ments, smaller quantities have little such effect. Calomel has no action 
on the digestive ferments, but retards the putrefaction in the intestine, 
and thus limits the decomposition of the food. Its antiseptic action 
is aided by the increased peristalsis which follows its use, and which 
removes the decomposing mass from the canal. In fact, the lessened 
amount of double sulphates in the urine which follows the use of 
calomel, may be ascribed as much to its purgative, as to its antiseptic 
power. 

Another organ which is powerfully affected by mercury is the Kid- 
ney. A moderate dose of calomel induces marked diuresis, particu- 
larly in cases in which there is a large accumulation of fluid in the 
body, as in dropsy from heart disease. In other forms of dropsy, 
such as that arising from hepatic cirrhosis, or from renal disease, it is 
less reliable, although it not infrequently increases the flow of urine in 
these cases also. When purging follows the administration of the 
mercurial, less diuretic effect is observed. 

In normal individuals and in animals the diuretic action is gener- 
ally much weaker, although some recent work has shown that it can 
be elicited easily in rabbits (Cohnstein). In view of the fact that 
mercurial preparations have an irritant action on the kidney, it would 
seem that the increased secretion of urine induced by calomel and In- 
other mercurials is most probably to be ascribed to a direct action on 
the epithelium. 

In acute mercurial poisoning, when death does not follow in the 
course of a few hours, anuria is often observed both in man and animals. 
This anuria is due to the renal changes, which arc found to consist in 
necrosis of the epithelium of the tubules in some parts of the cortex. 
The whole organ is congested and the glomeruli arc in a state of acute 



b*46 THE HEAVY METALS. 

inflammation, but the necrosed tubules are the most prominent feature. 
Very generally in the rabbit, less often in the dog and in man, these 
are filled with a deposit of phosphate of calcium, occasionally in- 
termixed with some chalk. According to some pathologists, it is 
deposited first in the tubules and only when these are filled does it 
force its way into the cells, but a more probable view is that it is thrown 
out in the necrosed cells, and as these break up, passes into the tubules. 
It may be remarked in passing that several other poisons, such as bis- 
muth and aloin, occasionally induce this deposit of lime in the 
kidneys. 

These renal symptoms have been observed most frequently in cor- 
rosive sublimate poisoning, either by the mouth, or from absorption 
from a wound. The more slowly absorbed, insoluble preparations ap- 
parently do not often accumulate in sufficient quantity in the blood to 
induce such severe effects. At the same time, albumin or casts are 
very often observed in the urine from the treatment of syphilitic pa- 
tients with mercury in any form, although it is stated that this is less 
liable to occur when soluble preparations are injected hypodermically 
than after inunction or the use of insoluble salts subcutaneously. The 
more marked the action on the intestine, the less destruction of the 
kidney is observed in cases of severe poisoning. 

The lime deposited in the kidney has suggested the idea that mercury has 
a specific action on Bone, consisting in the absorption of the calcium, and an 
attempt has been made to demonstrate this action by estimating the lime 
salts in bone after mercury, and comparing the amount with that of normal 
animals of the same size. In addition, some of the earlier writers mention a 
congestion of the bone marrow in chronic mercury poisoning. No action on 
bone has been established however, and the explanation of the renal deposit 
as due to decalcification of the bones has been shown to be incorrect by 
Klemperer, who found that, instead of being oversaturated with lime which 
it deposits in the kidney, the blood actually contains a somewhat smaller 
amount of lime than normally. The lime deposited in the kidney is evidently 
drawn from that normally circulating in the blood ; in necrosed tissue from 
other causes lime is very often deposited, although not so rapidly as in 
mercury poisoning. 

Mercury seems to have comparatively little direct action on the 
Circulation in cases of poisoning, and most of the changes in the pulse 
are to be ascribed rather to the shock and collapse, or in chronic 
poisoning to the cachexia and malnutrition, than to any direct effects 
on the heart and vessels ; in some cases of acute poisoning, however, 
patches of fatty degeneration have been found in the heart. In the 
frog large doses of soluble salts slow and weaken the heart, and mer- 
cury salts injected into the blood vessels of mammals have been found 
to cause a sudden descent of the blood-pressure and paralysis of the 
heart. Subcutaneously injected into animals, the soluble salts reduce 
the blood-pressure more gradually, but at the end a very sudden de- 
scent to zero occurs. The action is in part on the heart muscle, in 
part on the peripheral vessels. 



MERCURY. 647 

The Respiration is also only affected indirectly. In chronic mer- 
cury poisoning, marked breathlessness is sometimes observed and has 
been ascribed by Kussmaul to the general muscular weakness. 

The action of mercury on the Nervous System is very obscure. In 
acute poisoning the intellect often remains clear to the end, and no 
symptoms pointing to any direct affection of the central nervous 
system are observed. In chronic poisoning, however, the higher cen- 
tres are undoubtedly involved in the effects, as is shown by the 
erethism and occasional hallucinations. The tremor is also of cerebral 
origin probably, though this is not yet certain, and the general muscular 
weakness is not due to the peripheral muscles and nerves being affected, 
but to the alterations in the centres. As regards the paralysis sometimes 
observed in the arms or legs in workers in mercury, Letulle believes it to 
be caused by the poison acting on the peripheral nerves and destroying 
the myeline sheath. The areas of partial anaesthesia and the pains in 
joints may also prove to be due to peripheral changes. In some cases, 
especially where the tremor is marked, the reflex excitability of the 
spinal cord has been found to be exaggerated, but it is generally unaf- 
fected. The muscles do not seem to be acted on directly in either 
acute or chronic poisoning in man, and even when paralysis is de- 
veloped, they maintain their irritability and do not atrophy. In the 
frog mercury weakens the muscles, but only after doses which are suf- 
ficient to paralyze both the central nervous system and the heart. 

A good deal of interest has been manifested in the question whether 
mercury affects the Nutrition in any way except through its action on 
the alimentary canal. Several authors have stated that the urea is in- 
creased by the use of small doses, but the subject is a very difficult 
one to investigate, for when any save the smallest doses are given, the 
kidney and bowel are involved in the effects, and the prolonged use of 
mercury is restricted to experiments on animals and on syphilitics. 
There seems, however, good reason to believe that very small doses of 
mercury given for some time increase the nutrition and weight of ani- 
mals. The cachexia of chronic poisoning may be due in part to a 
specific action on the metabolism, but it is impossible to determine 
this point, because the alterations in the alimentary tract are in them- 
selves sufficient to cause such symptoms. Meyer found that mercury 
lessened to some extent the alkalinity of the blood, probably by the 
formation of lactic acid in excess. 

Changes in the Blood Corpuscles have been observed under mercurial 
treatment in a number of instances, but there is as vet no general 
agreement as to wherein these consist, and it seems not unlikely that 
the blood reaction in health is different from that in syphilis and that 
it may vary in the successive stages of the disease. In health the red 
corpuscles and the haemoglobin arc said to be augmented at first but 
afterwards diminished, while in syphilis a sharp fall in the amount of 
haemoglobin is succeeded by an increase to beyond that present before 
the treatment. Kuperwasser states that in healthy persons mercury 
increases the number of newly formed leucocytes but that this is more 



<348 THE HEAVY METALS. 

than counterbalanced by the fall in the older cells; in syphilis be 
found fewer recently formed leucocytes and more mature ones after 
mercury. 1 

Mercury has no effect on the Temperature in itself, but when sto- 
matitis or skin eruptions are developed, some fever generally accom- 
panies them, while in collapse the temperature may fall several degrees 
below the normal. 

Distribution. — After its prolonged use mercury is found in almost 
every organ of the body, but larger quantities are found in the kidney 
and liver than elsewhere, and it seems to be stored in these organs 
longer than in any other. In cases of acute poisoning through ab- 
sorption from the subcutaneous tissue or from wounded surfaces, the 
distribution is the same. The statement that mercury is stored up in 
large quantities in the bones has not been confirmed by the more re- 
cent investigators, but traces are found here, as in the muscles, brain, 
lungs, intestine and spleen. 

Mercury is Eliminated by almost all the excretory organs, but most 
largely by the intestine and kidney. It has been found in small quan- 
tities in the perspiration, milk, saliva, gastric juice and bile, and has 
been shown to pass to the foetus in utero through the placental circu- 
lation. The excretion begins within one or two days after absorption, 
but is very slow and irregular. Mercury has certainly been found in 
the urine six months after its administration had been stopped, and 
some authors state that it may be detected in it for years afterwards. 
It is open to question, however, whether these last cases of very pro- 
longed excretion are not to be explained by the patients having been 
exposed to the fumes of mercury in the interim. At the same time it 
is not impossible that pockets of mercury may be encapsuled in the 
tissues when the insoluble preparations are injected, exactly as a lead 
bullet may be, and that after a long time some irritation such as a blow 
may again liberate it and permit of its excretion. The elimination 
is said to last longer when the mercury is rubbed into the skin than 
when it is given by the mouth, or when soluble preparations are in- 
jected hypodermically. This is explained by the drug passing more 
slowly through the skin, which continues to contain some of it long 
after the inunction treatment has ceased. Mercury often disappears 
from the urine for several days or even weeks at a time, and then re- 
turns again. It is said that more mercury is found in the urine after 
its hypodermic injection than after inunction, but even in the most 
favorable circumstances only a small proportion of that absorbed is 
excreted by the kidneys. In the urine the mercury probably exists 
for the most part in the form of a salt, although some of it may be 
in organic combination. 



1 Many of the lesions of acute mercury poisoning have been stated by Kaufmann to 
be due to the formation of capillary emboli in the kidney and intestine. This expla- 
nation has been contested by several authors, and seems to be no more firmly estab» 
lished than the similar statement regarding the effects of phosphorus and arsenic. 



MERCURY. 649 

Mercury forms very poisonous compounds with methyl and ethyl, which 
are apparently very slowly decomposed in the organism to ordinary forms, 
and which have given rise to fatal poisoning in two cases, the symptoms 
making their appearance only long after the ingestion. 1 

Therapeutic Uses. — The chief purpose for which mercury is used in- 
ternally, is the treatment of Syphilis. Its curative effects in this dis- 
ease can be explained at present only by supposing that it develops a 
specific destructive action on the syphilitic virus. 2 Its virtues are 
attested by the great majority of the medical profession, but a com- 
paratively small minority still oppose its use, and some have even 
gone so far as to assert that instead of curing syphilis it promotes the 
development of tertiary symptoms. Less extreme opponents of the 
mercurial treatment hold that, while the secondary symptoms cer- 
tainly disappear under it, they are only rendered latent, and reappear 
in course of time, whereas without mercury they would have run 
their course in the first instance and disappeared. There is no ques- 
tion that a certain proportion of cases of syphilis recover without the 
use of mercury, and indeed without the use of any drug. In many 
of these, however, the course of the disease can be shortened by mer- 
cury, and in many others, in which the symptoms show no signs of 
abating under hygienic measures, mercury causes a rapid and perma- 
nent improvement. A certain number of relapses undoubtedly occur 
after the mercurial treatment has been left off, but it seems probable 
that many of these would not have had even temporary relief without 
mercury. As to the old argument that tertiary syphilis is caused by 
the use of mercury in the earlier stages, it has been shown that tertiary 
syphilis occurs without mercury, and that the lesions caused in it are 
entirely different from those induced by this metal. The opponents of 
mercurial treatment frequently assume that it is necessarily followed 
by cachexia and by all the lasting disorders which its abuse leads to. 
At the present time, however, mercury is administered in small quan- 
tities, and sy philologists are agreed that it ought not to be allowed to 
induce any but the earliest symptoms of chronic poisoning. To sum- 
marize the view held by the great majority of authorities, it may be 
said that mercury is of benefit in a very large proportion of cases, 
although it is not essential to the treatment of some favorable ones, 
and that it is unable to arrest the progress of the disease in a certain 
proportion of malignant forms. 

A question that is still debated, and which, like the other matters of 
doubt concerning the mercurial treatment of syphilis, has given rise to 
an overwhelming literature, is whether mercury ought to be exhibited 
as soon as the diagnosis of primary syphilis is made, or whether the 
advent of the secondary stage is to be awaited. Practice differs in this 
respect, but probably the majority of physicians do not prescribe mer- 
cury until some secondary symptom makes its appearance, and then 
continue its administration until the disease disappears, or until sali- 

l Hepp, Arch. f. exp. Path. u. Pharm., xxiii., p. 91. 

2 There is some evidence that the administration of mercury to animals slightly in- 
creases their resistance to subsequent infection with anthrax for some time | (Jasfa ). 



650 THE HEAVY METALS. 

vation or stomatitis warns against its further use. Some authorities 
recommend that mercury be continued for months after the secondary 
symptoms have been relieved, in order to prevent relapse, but this is 
less rigidly carried out now than in the earlier decades of last century. 
In tertiary syphilis mercury is generally considered inferior to the 
iodides, but when the disease attacks any important organ, such as the 
brain or eye, mercury is more reliable, or both mercury and iodide may 
be prescribed together. In hereditary syphilis mercury is much more 
efficient than iodides. 

Mercury has been used in syphilis in a large number of forms, and 
of late years new preparations and new methods of administration 
have succeeded each other so rapidly that it is impossible to discuss 
them all. Formerly mercury was given by the mouth or by inunction, 
and apart from the special clinics and the syphilologists, the internal 
treatment is still the most popular one. The preparations generally 
used for internal administration are corrosive sublimate, calomel, or 
the metallic preparations — blue pill and gray powder — the last being 
used most widely in England. Calomel and the metallic preparations 
are, however, very liable to induce diarrhoea, from their being insoluble 
and thus passing into the intestine before being absorbed, and opium 
is therefore often prescribed along with them. Calomel is also credited 
with causing salivation and stomatitis more readily than the other 
preparations, perhaps because it is more difficult to gauge how much 
of it is absorbed than in the case of the soluble perchloride. Mercury 
administered by the mouth is in all cases more liable to derange the 
digestion than when administered by other channels. Accordingly, 
inunction was introduced to avoid the disturbance of the stomach and 
intestine caused by the local action of the mercury, while that due to 
its excretion along the alimentary tract remained unchanged. By this 
method the mercury is rubbed into the skin in the form of ointment ; 
that most frequently used consists of metallic mercury suspended in a 
state of fine division in lard, but others have been suggested, such as 
the oleate of mercury, the ointment of the yellow oxide, and mercury 
soaps. The first is less irritant, however, and has entirely supplanted 
the others, which never enjoyed a very wide popularity. The action 
of mercury is somewhat more slowly elicited by this method than when 
it is administered internally, but lasts longer, and the digestion is less 
liable to be disturbed. The mercury is absorbed in the form of a 
proteid combination from the gland ducts, and probably a small quan- 
tity is inhaled by the lungs as vapor. The objection to the method is 
that it is inconvenient and uncleanly, and that it is even less possible 
to estimate the amount of mercury actually absorbed than when it is 
given by the mouth. One case of fatal poisoning has been recorded 
from the ointment being applied to sore hands. Instead of mercury 
ointment being rubbed into the skin, one of the plasters or lint con- 
taining mercurial ointment (Weylander) may be applied to it, permit- 
ting of the continuous absorption of small quantities by the skin and 
by inhalation of the vapor. 



MERCURY. 051 

In 1867, Lewin introduced a new method, the hypodermic injection 
of a dilute solution of corrosive sublimate, and this has been very 
widely practised of late years, and with great success. The advantages 
of the method are the avoidance of digestive disturbance, which is 
shared by the inunction method, its cleanliness, the more accurate esti- 
mation of the amount of mercury actually administered, and the greater 
rapidity of action. Its chief disadvantage is the pain caused by the 
injection, which has to be repeated daily ; some inflammation and 
swelling follow immediately, but no suppuration, when ordinary care 
is taken ; but the pain is very intense and persistent and many patients 
refuse to continue the treatment. Salivation is said to follow this 
method more seldom than any other, and relief from the secondarv 
syphilitic symptoms is gained sooner. Lewin continues to use the per- 
chloride solution and prefers it to any of the modifications ; others 
have added morphine, or, more recently, cocaine, in order to lessen the 
pain, but this is to be deprecated from the danger of the habit being 
formed. The addition of chloride of sodium tends to prevent the pre- 
cipitation of proteids by the perchloride, and a solution of perchloride 
of mercury, with ten times its weight of common salt or of urea has 
therefore been advocated, while others have used the peptonate or the 
albuminate of mercury dissolved in salt solution. Mercury has a strong 
affinity for the amido-group, and in combination with it has little ten- 
dency to precipitate proteids, and this has led to the use of preparations 
of mercury with the amido-acids, such as glycocoll, formamide or suc- 
cinimide. Many of these methods are said to lessen the pain of hypo- 
dermic injection, but do not remove it entirely, probably because the 
various compounds undergo some dissociation in the tissues, and the 
free mercury ion causes the same irritation as if the perchloride had 
been injected. 

Instead of the soluble preparations of mercury, which necessitate 
the painful injections being repeated daily, insoluble salts have been 
injected, with the idea that these being slowly dissolved and absorbed 
from the seat of injection, a quantity sufficient for several days may 
thus be given at one time. Instead of injecting these insoluble prep- 
arations hypodermically, they are often thrown into the muscular tissue. 
According to the advocates of this method, it causes less immediate pain 
than perchloride injections, but, as solution takes place, and the mer- 
cury attacks the tissues, the part becomes extremely painful, swollen, 
and inflamed. Suppuration and even gangrene have been developed 
in a very considerable number of cases, and in others severe or fatal 
mercury poisoning has been observed. The advantages of the method 
are that the physician has not to visit the patient every day, and that 
the injection need only be made once, or at most twice a week. On 
the other hand, the local lesions are often very severe, and the amount 
of mercury absorbed cannot be controlled in any way. It has the ad- 
vantage over the administration per os that the digestion is not so 
liable to be interfered with, but, as has been said, the danger and 
pain are very much greater. Many authorities therefore deprecate 



652 THE HEAVY METALS. 

the use of these insoluble preparations by injection, but a considerable 
number of syphilologists still persist in their use, and new preparations 
have been introduced for this purpose in large numbers. Those most 
commonly used are calomel in salt solution or in liquid paraffin, me- 
tallic mercury in very fine division suspended in liquid paraffin, the 
salicylate, benzoate, and the thymol-acetate. The oxides have also 
been proposed and many other preparations have received a trial by 
this method. 

Other methods of introducing mercury into the tissues are more rarely 
employed. The intravenous injection of the perchloride has been suggested 
for the treatment of cases in which there is urgent haste, but has rarely been 
carried out, and is likely to prove dangerous from the formation of emboli, 
and also from the effects of mercury on the heart when thus applied. 

Suppositories of mercury have been used to some extent, and are said to 
disturb the digestion less than the administration per os. 

Mercury fumigations have also been practised to a limited extent, the 
vapor of mercury being freed by heating calomel or the sulphide. The pa- 
tient sits in a wooden tent up to his neck and the mercury deposited on the 
skin is absorbed. The method is very cumbrous, and the quantity of mer- 
cury taken up cannot be controlled. 

Mercury was recommended by Hamilton in the beginning of last 
century in the treatment of Acute Febrile Affections, and the greatest 
abuse unquestionably prevailed in the earlier decades. Later its 
sphere of usefulness was restricted to the treatment of inflammation of 
the serous membranes — pleurisy, meningitis, pericarditis, peritonitis — 
and many physicians still maintain that it checks the effusion and pro- 
motes the healing of these diseases. Others deny that mercury pos- 
sesses any virtues in these cases, and its use is undoubtedly becoming 
more limited ; in acute iritis it is still used almost universally. In 
these cases it is always administered by the mouth in the form of 
calomel, blue pill or gray powder. 

As a Purgative mercury is very frequently prescribed in " bilious- 
ness," and in putrefactive diarrhoea. It acts partly from its antiseptic 
power, but mainly by removing the putrefying contents from the in- 
testine ; calomel, blue pill or gray powder is usually employed with 
or without the addition of a vegetable purge. 

Calomel has proved of only doubtful value as an intestinal antisep- 
tic in typhoid fever, dysentery and other similar conditions. 

Calomel and other mercurials have long been known to be of value 
in cases of Dropsy, but Jendrassik deserves the credit of having re- 
vived their employment as diuretics, for this use of mercury had fallen 
into oblivion. The best preparation is calomel, given in 0.2 G. (3 
grs.) doses three times a day or in 0.1 G. (2 grs.) doses 5-10 times a 
day. It is of great value in certain cases of cardiac dropsy, but is 
less reliable in the accumulations of fluid met with in hepatic or renal 
disease, although here too its administration is sometimes followed by 
the rapid excretion of the fluid. It does not seem to be contraindi- 
cated in chronic nephritis, although its action has to be carefully con- 



MERCURY. 653 

trolled. It has no effect in removing the exudations of acute inflam- 
mation such as pleurisy. 

Mercury is used Externally as an Antiseptic wash in surgical opera- 
tions, chiefly in the form of the perchloride, but also as the cyanide 
and oxy cyanide. It is irritant to wounds, however, and is liable to be 
absorbed when applied to large surfaces, and several cases of fatal 
poisoning have been recorded from the use of even the most dilute 
solutions of corrosive sublimate to wash out the uterus and vagina. 
These preparations, more especially the perchloride, have also the dis- 
advantage of attacking steel instruments. 

Numerous ointments have been applied externally in the treatment 
of Skin Diseases, particularly those of a parasitic nature, such as itch, 
and in condylomata, ulcers and skin diseases of syphilitic origin. 
These preparations combine an antiseptic with a more or less irritant 
action, and unlike carbolic acid and its allies, are equally powerful 
antiseptics in ointments and in water. The least irritant of the phar- 
macopceial ointments is the mercury ointment ; then the oleate, yel- 
low oxide, red oxide, and ammoniated mercury follow in order, while 
citrine ointment is much more irritant and corrosive. Other external 
applications are the plasters and the black and yellow wash. Oint- 
ments containing calomel, corrosive sublimate, and other preparations 
are sometimes prescribed, or calomel may be used as a dusting powder 
in syphilitic ulcers. The mercury ointments are frequently applied to 
the eye, the milder ones as antiseptics and slight irritants, citrine oint- 
ment to destroy granulations. 

Mercurial ointments are sometimes employed to promote the absorp- 
tion of subcutaneous effusions and to reduce swellings. They are not 
superior to other irritants for this purpose, however, and have the dis- 
advantage of permitting the absorption of a dangerous poison. 

The nitrate of mercury and its ointment (citrine) are sometimes used 
as caustics for application to the os uteri, condylomata and elsewhere. 

Mercury treatment is Contraindicated, or requires special caution in 
cases of profound cachexia, weakness, or ansemia, unless these arise 
from syphilis. Where the digestion is weak, it ought to be avoided if 
possible, and in cases of tuberculosis there is always the danger that 
the disturbance of the digestion may accelerate the course of the dis- 
ease. In severe nephritis it is also to be used with caution, although 
it is beneficial in some cases, and although some authorities deny that 
it is injurious even when it has no diuretic action. In pregnancy mer- 
cury is not absolutely contraindicated, at any rate up to the sixth 
month. Later it is liable to injure the patient by its action on the di- 
gestion, and in some cases has induced abortion ; the child may also 
suffer from mercurial poisoning. Mercurial ointments or dusting 
powders have to be used with care when iodides are being administered 
internally, as the iodide excreted forms the iodide of mercury, and 
this may cause violent corrosion. Thus in the eye, severe effects have 
been induced by the application of calomel to the cornea while iodide 
was being given. 



054 THE HEAVY METALS. 

In cases of Acute Corrosive Poisoning, the indications are the evac- 
uation of the stomach, preferably by the stomach tube. Tannic acid, 
or eggs, milk and other albuminous substances may be given to pre- 
cipitate the metal and protect the mucous membrane. The treatment 
of the later symptoms is the same as that of the chronic form. 

In Chronic Poisoning the salivation and stomatitis arc treated r>y the 
use of chlorate of potash solution as a mouth wash, and its free applica- 
tion during mercurial treatment, along with careful brushing of the 
teeth, is believed by most physicians to hinder the onset of the 
symptoms. Tannic acid solution is also recommended as a mouth wash. 
The diarrhoea may be treated with opium, the other symptoms on 
general principles. In any case the drug ought to be abandoned, or 
the dose much reduced as soon as the salivation becomes marked. In 
chronic poisoning not arising from the therapeutic use of the drug, 
iodide of potassium is generally prescribed, although its utility has not 
yet been placed beyond question. Sulphur baths, and hot baths 
without sulphur are also recommended. 

Preparations. 

Hydrargyri Chloridum Corrosivum (U. S. P.), Hydrargyri Per- 
chloridum (B. P.), corrosive sublimate (HgCl 2 ), forms heavy, colorless 
crystals, without odor, but possessing an aerid, metallic taste, soluble in 16 
parts of cold water, in 2 parts of boiling water, in 3 rjarts of alcohol, and 
in 4 parts of ether. 

Liquor Hydrargyri Perchloridi (B. P.) contains & gr. in a fluid 
dr., $-1 fl. dr. 

Corrosive sublimate is one of the most irritant preparations, and is rapidly 
absorbed. It is used internally in syphilis, 0.002-0.02 G. (jj-i gr.), 1 in one 
per cent, solution and is also injected hypodermically in 0.6 per cent, solu- 
tion, 2 c.c. (30 mins.) daily. This solution is often made up with 6 per cent, 
of sodium chloride or urea. Perchloride of mercury is less liable to induce 
salivation, but disturbs the digestion more than other preparations when 
given internally, while its hypodermic injection is exceedingly painful. It 
has induced fatal poisoning in the dose of 0.18 G. (3 grs.), taken by the 
mouth, but in other cases much larger quantities have been recovered from. 
It is stated that opium eaters can take enormous quantities without evil 
effects. 

It is used extensively in surgery as an antiseptic solution (1 in 2,000-4,000), 
to disinfect the hands, wounds, etc., but is irritant to delicate tissues, such 
as the peritoneum, and corrodes steel instruments. It is also used in the 
form of a soap and to impregnate bandages, cotton-wool, gauze, catgut 
and silk. It preserves its antiseptic action in oils and ointments. It has 
been used to a limited extent in skin diseases in solution, in baths, or in 
ointment, as a local application in diphtheria, and as an intestinal antiseptic 
in putrefactive diarrhoea, typhoid fever and cholera. 

The albuminate and peptonate of mercury are formed by precipitating a 
solution of egg albumin or of meat peptone with a five per cent, solution of 
corrosive sublimate. The precipitate is collected, washed and dissolved in 
20 per cent, chloride of sodium solution. It was hoped that these prepara- 
tions would not cause irritation and pain when injected subcutaneously, but 
this anticipation has not been fulfilled and they have fallen into almost 
complete disuse. They are not official. 

Hydrargyri Cyanidum (U. S. P.), mercuric cyanide (Hg(CN) 2 ), colorless 

1 The B. P. gives as the dose of corrosive sublimate and the red iodide, /—tV g r - 



MERCURY. 655 

crystals, without odor and with a bitter, metallic taste, soluble in about 12 
parts of water, in 15 parts of alcohol. The cyanide resembles the perchlo- 
ride in its action and has been used hypodermically in syphilis. As a surgical 
antiseptic it is equal to corrosive sublimate and attacks steel instruments 
less. Dose, as of corrosive sublimate. 

The oxy cyanide of mercury (Hg 2 0(CN) 2 , > is also used to form an antiseptic 
lotion in surgery. The double cyanide of mercury and zinc has been recom- 
mended by Lister for this purpose. 

Hydrargyri Iodidum Rubrum (U. S. P., B. P.), red iodide of mercury, 
biniodide of mercury (Hgl 2 ), a scarlet-red, amorphous powder, tasteless and 
odorless, almost insoluble in water, but soluble in solution of iodide of po- 
tassium. 0.005-0.02 G. (*V-i gr.), (B. P. sWV gr.). 

This preparation is very seldom prescribed as such, but is frequently 
formed by prescribing a mixture of corrosive sublimate and potassic iodide, 
when the iodide of mercury is formed and is kept in solution by the excess of 
the iodide of potassium. This prescription is often indicated in the transi- 
tional period between secondary and tertiary syphilis, and even when the 
tertiary symptoms are fully developed. 

Liquor Arseni et Hydrargyri Iodidi (U. S. P., B. P.), Donovan's solution, 
contains one per cent, each of arsenic iodide and red mercuric iodide. Used 
as a tonic in syphilitic and other cases. 0.3-1.3 c.c. (5-20 mins.). 

Unguentum Hydrargyri Iodidi Rubri (B. P.), 4 per cent. 

Hydrargyri Chloridum Mite (U. S. P.), Hydrargyri Subchloridum 
(B. P.), mild mercurous chloride, calomel (Hg 2 Cl 2 ), a heavy white powder 
without odor or taste, insoluble in water, alcohol and ether. 0.03-0.3 G. 
(£-5 grs.) in powder, less suitably in pill form. 

Pilulse Antimonii Composita (U. S. P.), Pilula Hydrargyri Subchloridi Com' 
posita (B. P.). See Antimony, page 637. 

Unguentum Hydrargyri Subchloridi (B. P.), 10 per cent. 

Calomel is contained in the compound cathartic pill U. S. P. (p. 106). 

Calomel is used in syphilis (dose, 0.05 G. (1 gr.) thrice daily), but is credited 
with being more liable to induce salivation than other preparations, and its 
purgative action often has to be counteracted by opium. It has also been 
injected subcutaneously in suspension in 10 per cent, salt solution, or in 
liquid paraffin, but has many disadvantages compared with the soluble 
preparations. As a purge and intestinal disinfectant, it is of value in bilious- 
ness, and in the diarrhoea of putrefaction, less so in diseases in which the 
intestinal wall is the site of infection, as in typhoid fever and cholera. Calo- 
mel causes less irritation and colic than most other purges, and small doses 
are followed by only one evacuation. It may therefore be given where pre- 
existing irritation of the intestine contraindicates the use of most other pur- 
gatives. Calomel is often advised in hepatic affections, but it is a question 
whether it has any effect here except as a purge. It is of great value in some 
forms of dropsy, especially those of cardiac origin, in which it is administered 
in 0.2 G. (3 gr.) doses thrice a day for 2-4 days, and is stopped as soon as 
the diuresis sets in. The treatment may be repeated if the dropsy returns. 
Alkalies are often added to calomel prescriptions on the ground that in this 
way there is less danger of the calomel being changed to corrosive sublimate 
in the stomach. For the same reason, acids are often avoided for some time 
after calomel is taken. As a matter of fact these fears are quite groundless, 
as calomel is not changed to the prechloride in the stomach and it is there- 
fore quite unnecessary to add alkalies to calomel. 

Calomel has been used externally as a dusting powder for syphilitic 
condylomata, as a slight irritant to the cornea and as an ointment in pruritus 
and other skin diseases. 

Hydrargyri Iodidum Flavum (U, S. P.), yellow or green iodide of mercury 
(Hg„I 2 ), a bright yellow amorphous powder, tasteless and odorless, insoluble 
in water, alcohol or ether. 



656 THE HEAVY METALS. 

It has been used in syphilis, with the idea of uniting the virtues of the 
iodides and of mercury. But the quantity of iodide is altogether inadequate 
0.05-0.2 G. (1-3 grs.). 

Hydrargyrum cum Creta (U. S. P., B. P.), mercury with chalk, gray 
powder, is formed by rubbing up metallic mercury with chalk and honey 
(U. S. P.) until the mercury is divided into very fine globules, each encased 
in chalk. It forms a light-gray, somewhat damp powder, without odor and 
with a sweetish taste from the honey. The mercury (38 per cent. U. S. P. , 
33 per cent. B. P.), remains in the metallic state, very little oxide being 
formed. It is insoluble in water, alcohol and ether, and is always prescribed 
in powder form. 0.1-0.5 G. (2-8 grs.). 

Massa Hydrargyri (U. S. P.), mass of mercury, blue mass, blue pill, 
is formed from metallic mercury by rubbing it with Mel Rosas, glycerin, al- 
thaea and liquorice until the globules are invisible under a lens magnifying 
ten diameters. The blue mass contains about 33 per cent, of mercury almost 
entirely in the metallic form. It is of the consistency of pills and is always 
prescribed in this form. 0.2-0.5 G. (3-8 grs.). 

Pilula Hydrargyri, blue pill, the corresponding B. P. preparation, 
is made up with confection of roses and liquorice by rubbing them with 
metallic mercury until the globules are no longer visible. 4-8 grs. 

These preparations are very largely used as mild mercurial purgatives, 
the blue pill being frequently reinforced by the addition of one of the vege- 
table purges. The gray powder is especially adapted for children, and is of 
value in summer diarrhoea and other similar conditions. Blue pill is often 
given in cardiac dropsy along with squills or digitalis, but has proved inferior 
to calomel as a diuretic. Gray powder is held by some authorities to be the 
best form for the internal treatment of syphilis, and is given in doses of 0.05 
G. (1 gr.) 3 to 5 times a day ; if necessary, opium may be given to prevent 
purging. The blue pill may also be used in syphilis and is less liable to purge. 

Unguentum Hydrargyri (U. S. P., B. P.), mercurial ointment, blue 
ointment, is formed by triturating metallic mercury w r ith lard and suet and 
oleate of mercury until the globules are invisible when magnified ten diam- 
eters. The ointment contains about one half its weight of metallic mercury 
along with a small proportion of oleate. 

Unguentum Hydrargyri Compositum (B. P.) contains camphor and is some- 
what weaker than blue ointment. 

The famous blue ointment is used largely in many forms of skin diseases, 
especially in those of syphilitic origin, and was formerly the ordinary treat- 
ment for scabies, in which, however, it has been supplanted by balsam of Peru 
and other remedies, though it is still used occasionally to destroy pediculi. 
The most important purpose for which blue ointment is applied at the pres- 
ent time is the treatment of syphilis by inunction. For this purpose 2-4 G. 
(^-1 dr.) is rubbed in daily in different parts of the body, in order to avoid 
the irritation induced by applying it repeatedly to one spot. A warm bath 
is taken first, and the patient then rubs in the ointment on the inside of 
the thighs, next day on the inside of the arms, on the following days on 
the forearms, legs, abdomen and back, returning to the thighs on the seventh 
day and repeating the series. The treatment is continued for a fortnight or 
three weeks. This method has the advantage that the digestion is less af- 
fected than when the drug is given internally, but on the other hand, the mer- 
cury is more slowly absorbed than by other methods ; and no estimate of the 
quantity really taken up can be formed, as, although the patient is directed 
to rub it in until the whole disappears, the instructions may be imperfectly 
carried out. Salivation is not so readily produced as by the administration 
per os, but when it occurs, it lasts longer and may become severe. One case 
of fatal poisoning has been recorded from the application of the ointment, but 
in this case the skin appears to have been broken. Skin rashes are more fre- 
quent from inunction than from any other method of application, and finally, 



MERCURY. 657 

the method is extremely inconvenient and dirty. The patient ought to carry 
out the inunction himself, for any other person doing so may acquire chronic 
poisoning from absorption through the hands, and even if this is prevented 
by the use of gloves of India-rubber or oiled bladder, some mercury may be 
absorbed by the lungs. In children the ointment is often applied by spread- 
ing it on a bandage, which is then applied around the waist. In skin disease 
and in very hirsute individuals, the inunction treatment is impossible. 

Blue ointment diluted with oil, oleum cinereum, has been injected hypo- 
dermically, or into the muscles in the treatment of syphilis, but this method 
of treatment is even inferior to the injection of calomel, and in a large num- 
ber of cases gives rise to abscesses, and gangrenous sores. 

Oleaium Hydrargyri (U. S. P.), Hydrargyri Oleas (B. P.), oleate of mercury, 
has been used for the same purposes as mercury ointment, but is somewhat 
more irritant and possesses no compensating virtues. 

Unguentum Hydrargyri Oleatis (B. P.), 1 part in 4. 

Emplastrum Hydrargyri (U. S. P., B. P.), mercury plaster, is formed in the 
same way as the ointment by the trituration of metallic mercury. 

Emplastrum Ammoniaci cum Hydrargyro (U. S. P., B. P.) is similarly formed 
but contains less mercury and a large quantity of a gum-resin (ammoniac). 

These plasters are sometimes applied to chancres and to syphilitic ulcers, 
and mercury plaster has been applied instead of the ointment as a treatment 
of syphilis. 

Linimentum Hydrargyri (B. P.). 

Hydrargyri Oxidum Flavum (U. S. P., B. P.), yellow mercuric oxide. 

Hydrargyri Oxidum Rubrum (U. S. P., B. P.), red mercuric oxide. 

Unguentum Hydrargyri Oxidi Flavi (U. S. P. 10 per cent., B. P. 2 
per cent.). 

Unguentum Hydrargyri Oxidi Rubri (U. S. P., B. P.), 10 per cent. 

The two oxides are identical in constitution (HgO), but the yellow is 
obtained by precipitation from the perchloride, the red by oxidation of the 
metal by means of nitric acid. The red is crystalline, the yellow amorphous, 
and both are practically insoluble in water and alcohol, but are soluble in 
acids. The red oxide is more irritant than the yellow on account of its 
crystalline form, and perhaps also because it often contains some nitrate. 
The yellow oxide is used in ointment in various diseases of the eye, and 
both are employed as applications to syphilitic sores, condylomata, and 
chancres, although the red is often preferred for this purpose. They have 
also been proposed for hypodermic injection suspended in water. 

Two famous preparations of mercury are the black and the yellow wash, 
the former prepared from calomel, the latter from corrosive sublimate by the 
action of lime water. The black wash, Lotto Hydrargyri Nigra (B. P.), con- 
tains mercurous oxide (Hg 2 0), the yellow, Lotto Hydrargyri Flava (B. P.), 
mercuric oxide (HgO). The oxides are in both cases insoluble and the 
lotions have to be shaken before application. They are used in syphilitic 
lesions as local remedies. 

Hydrargyrum Ammoniatum (U. S. P., B. P.), mercuric ammonium chloride, 
white precipitate (XH 2 HgCl), is formed by precipitating corrosive sublimate 
with ammonia, and is a white, amorphous powder, without odor and with 
an earthy, metallic taste, almost insoluble in water and alcohol. 

Unguentum Hydrargyri Ammoniati (U. S. P., B. P.), 10 per cent. 

The white precipitate is not used internally, and is more irritant than the 
oxides. The ointment is occasionally applied in skin diseases and bo destroy 
parasites. 

Hydrargyri Subsulphas Flavus (U. S. P.), basic mercuric subsulphate, Tnr- 
peth mineral (Hg(HgO) 2 SO) 4 , forms a heavy, lemon-colored powder, odorless 
and almost tasteless, practically insoluble in water and alcohol. 

The sulphate is scarcely used in medicine at the present day. It was at 



658 THE HEAVY METALS. 

one time recommended as an emetic in croup, as it irritates the stomach, 
but it is extremely dangerous to use it in this way. 

Liquor Hydrargyri Nitratis (U. 8. P., B. P.), solution of mercuric nitrate, 
contains about 60 per cent, of the nitrate (Hg(NO s ) 2 ) along with about 11 
per cent, of free nitric acid. It is a powerfully corrosive fluid which is used 
to cauterize the os uteri, cancers or condylomata. Symptoms of mercury 
poisoning have arisen from its application to the os uteri. 

Ungjuentum Hydrargyri Nitratis (U. S. P., B. P.), citrine ointment, 
is used, diluted with oil or lard, in conjunctivitis, and also as an application 
to syphilitic sores and gangrenous ulcers. 

XJnguentum Hydrargyri Citratis Dilutum (B. P.). 

Hydrargyrum (U. S. P., B. P.), metallic mercury, is not used in thera- 
peutics at the present time. It was formerly employed in cases of intestinal 
obstruction in large quantities (up to a pound or more) in order to drag the 
intestines into place by its weight. As a general rule no symptoms of poison- 
ing occurred, the mercury being voided unchanged and unabsorbed, but in 
some cases salivation followed its use. 

A large number of new preparations of mercury have been introduced of 
late years and have received a more or less extensive trial, but have seldom 
been found to be superior to the older forms. Among these may be mentioned 
the tannate, which was introduced in the hope that it would cause less pur- 
gation than calomel, and might therefore be better adapted for the treatment 
of syphilis. 0.1-0.3 G. (2-5 grs.) in powder. The carbolate, salicylate (either 
neutral or basic), benzoate, sozoiodolate, thymol-acetate and many other similar 
compounds have been used instead of calomel for hypodermic or intramus- 
cular injection, have each in succession been blazoned forth as the best 
preparation, and will probably be forgotten in the course of a few years. 
Several ami do acid salts of mercury such as the formamide, the amido-pro- 
pionate (alanin mercury) and the succinimide have been proposed as substi- 
tutes for corrosive sublimate in hypodermic injection. It was believed that 
the affinity of mercury for nitrogen being satisfied in these compounds, it 
would attack the proteids less, and as a matter of fact, the injections are 
said to be less painful than those of corrosive sublimate. Dreser has recently 
proposed mercuric-potassic hyposulphite, because the mercury is apparently 
contained in it in a form which does not admit of its dissociation. Colloid 
mercury has been suggested for inunction instead of the blue ointment. 

Bibliography. 

Chittenden. Johns Hopkins Hosp. Bull. 98, 1899. 

Saikowsky. Virchow's Arch., xxxvii., p. 346. 

Rosenbach. Ztschr. f. ration. Med., xxxiii., p. 36. 

Badziejewski. Arch. f. Anat. u. Phys., 1870, p. 55. 

Heilborn. Arch. f. exp. Path. u. Pharm., viii., p. 361. 

V. Mering. Ibid., xiii., p. 86. 

Meyer. Ibid., xvii., p. 304. 

Grawitz. Deutsch. med. Woch., 1888, p. 41. 

Keyes. Am. Journ. of Med. Scien., 1876, p. 17. 

JSchlesinger. Arch. f. exp. Path. u. Pharm., xiii., p. 317. 

Wilbouchewitch. Arch, de Physiol. , 1874, p. 509. 

Letulle. Arch, de Phys., 1887, i., p. 301. 

Rosenthal. Berl. klin. Woch., 1895, p. 500. 

Morel-Lavalle. Bev. de Med., 1891, p. 449. 

Jendrassik. Deutsch. Arch. f. klin. Med., xxxviii., p. 499; xlvii., p. 226. 

Bieganski. Ibid., xliii., p. 177. 

Stintzing. Ibid., xliii., p. 206. 

Sklodowski. Ibid., lii., p. 300. 

Bosenheim. Zts. f. klin. Med., xiv., p. 170. 

Cohnstein. Arch. f. exp. Path. u. Pharm., xxx., p. 132. 

Justus. Virchow's Arch., cxl., p. 91; cxlviii., p. 533. 

Kaufmann. Ibid., cxv., p. 71, and cxvii., p. 227. 



IRON. 659 



Klemperer. Ibid., cxviii., p. 445. 

Falkenberg u. Marchand. Ibid., cxxiii., p. 579. 

Neuberger. Ziegler's Beitrag zur path. Anat., vi., p. 429. 

Leutert. Fortschritte der Med., 1895, p. 89. 

Wassilieff. Zts. f. phys. Chein., vi., p. 112. 

B'ohm. Ibid., xv., p. 1. 

Welander. Arch. f. Derm. u. Syph., xxvi., p. 331. 

Pinner. Therap. Monatsh., 1889, p. 320. 

Lewin. Berl. klin. Woch., 1895, p. 245. 

V. Boeck. Ztschr. f. Biologie, v., p. 393. 

Paton. Brit. Med. Journ., 1886, i., p. 433. 

Kuperwasser. Arch, des Scienc. biol., vi., p. 325. 

Neumann. Practitioner, vii., p. 279. 

Piccardi. Arch. f. Derm. u. Syph., xli., p. 177. 

Winternitz. Arch. f. exp. Path. u. Pharm., xxv., p. 225. 

Ludwigu. Zillner. Wien. klin. Woch., 1889, p. 857. 

Wolff u. Nega. Deutsch. med. Woch., 1885, p. 847. 

Paschkis u. Vajda. Wien. med. Presse, 1881. 

Schuster. Deutsch. med. Woch., 1883, p. 193 ; 1884, p. 279. 

Dreser. Arch. f. exp. Path. u. Pharm., xxxii., p. 456. 

Quincke. Munch, med. Woch., xliii., 1896, p. 854. 

Marie. Arch. f. exp. Path. u. Pharm., iii., p. 397. 

Liebermann. PA tiger's Arch., liv., p. 573. 

Koch. Mittheil. a. d. Gesundheitsamte, i., p. 234. 

Geppert. Berl. klin. Woch., 1889, p. 789 ; 1890, p. 246. 

Gottstein. Therap. Monatsh., 1889, p. 102. 

Cathelineau. Arch. gen. de Med., clxxiv., p. 38. 

Schumacher. Arch. f. Derm. u. Syph., xliv., p. 189. 



III. IRON. 



Iron differs from the other heavy metals in being essential to the 
life of many, perhaps all, forms of protoplasm. In the vertebrates this 
is obscured by the fact that most of the iron is contained in the haemo- 
globin of the blood, and its importance in the other tissues is generally 
ignored. In the invertebrates, however, in many of which no corre- 
sponding compound exists in the blood, considerable amounts of iron 
are found in the tissues, and there is no question that throughout the 
animal kingdom iron is essential to living matter, quite apart from its 
special relation to the blood in the vertebrates. Molisch has shown 
that it is also necessary for the development of the lower vegetable 
forms, and it has been found that in its absence the higher plants fail 
to form chlorophyll, although iron is not actually contained in the 
latter as it is in haemoglobin. 

The iron combinations are generally divided into two classes — in- 
organic and organic. 1 In the former of these iron is contained in the 
ordinary salt form, is dissociated in solution, and can be recognized by 
such tests as the black precipitate with ammonium sulphide, and the 
blue precipitates with the ferrocyanide or ferricyanide of potassium. I n 
organic iron these tests fail, or are only elicited after prolonged contact, 
and this has been supposed to indicate that the iron is combined di- 

1 "Organic" and "inorganic" are here used in a special meaning, and have no 
reference to the combination to which iron is attached, but to the method of attach- 
ment. Thus the acetate and albuminate of iron are both classified among the inorganic 
iron compounds, because they are capable of dissociation, and the iron is precipitated 
by ammonium sulphide. "Masked iron" is a preferable term for "organic iron," 
but has not been so widely used. 



660 THE HEAVY METALS. 

rectly with the carbon of the preparation. Examples of inorganic 
iron are the chlorides, acetates or sulphates, while the best type of 
organic iron is haemoglobin, though numbers of others exist in the 
tissues. Between the ordinary salts of iron and haemoglobin and its 
allies, there exists a number of compounds, which are stained black by 
ammonium sulphide after prolonged contact, and which it is impossible 
to class either as organic or inorganic. 

When such a salt as the perchloride is added to a solution of proteid, 
it precipitates it at once in the form of iron albuminate. This insolu- 
ble body is also formed in the living tissues when the perchloride is 
brought in contact with them, and forms a protective coating on the 
surface. Iron has no such relation to the proteids as mercury, and 
does not corrode them of itself, any destruction which may be caused 
by such compounds as the perchloride being due to the acid constituent 
and not to the metallic ion. The albuminate is not so flocculent as 
that of mercury, and tends to protect the tissues from the acid, so that 
the corrosion of iron compounds is limited to the surface. The double 
salts of iron, the albuminous compounds, and organic iron do not pre- 
cipitate proteids, and are therefore neither irritant nor astringent as 
long as they maintain their original form and are not decomposed into 
simple salts. 

Symptoms. — Inorganic iron compounds, of which the perchloride 
may be taken as a type, have an astringent, metallic, or often acid 
taste, but in ordinary doses induce no further symptoms. If swal- 
lowed in large quantities, they cause pain and uneasiness in the stom- 
ach, nausea, vomiting and often purging, with all the ordinary symp- 
toms of acute gastro-intestinal irritation. General weakness and even 
collapse may be induced, but are manifestly secondary to the gastric 
and intestinal effects, and no symptoms which can in any way be at- 
tributed to the absorption of iron have been observed in either man 
or animals. 

The prolonged use of inorganic iron is frequently followed by some 
dyspepsia, and by constipation and colic, which are obviously due to 
the continued astringent action on the stomach and bowel. Other 
symptoms observed occasionally are blackness of the teeth and tender- 
ness in the gums, which may be due to the acid contained in many 
iron preparations ; the blackening of the teeth has been supposed to be 
due to the tannic acid of the food precipitating the inky black tannate 
of iron, or to the sulphide of iron being formed by the action of the 
hydrogen sulphide present in carious teeth. According to Buzdygan, 
the iron preparations increase the secretion of hydrochloric acid in the 
stomach, and may thus lead to hyperacidity, or aggravate it if already 
present. In artificial digestion, the salts of iron with organic acids 
are said to hinder the process more than those with inorganic acids, 
the ferric salts more than the ferrous, and the insoluble preparations 
least of all. The digestion of starch is almost unaffected by the pres- 
ence of iron. 

Iron given by the mouth induces leucocytosis (Pohl), and does not 



IRON. ' 661 

affect the amount of double sulphates excreted in the urine, so that it 
has no antiseptic action in the bowel (Morner). 

Some symptoms from the circulation are sometimes said to arise, but are 
for the most part subjective, and seem to be handed down by tradition rather 
than really observed. These are a feeling of congestion, fulness and heat in 
the head, and haemorrhages from the nose, throat and lungs, especially in 
phthisis. If these symptoms are not entirely imaginary, they are to be 
attributed to some reflex from the stomach and intestine and not to any 
direct action of iron on the heart or Vessels. 

When these astringent preparations are injected into the bloo r l vessels in 
animals, they coagulate the proteids and cause thrombosis but no real 
symptoms of iron poisoning. Fatal thrombosis has been observed in patients 
from the injection of the perchloride into the uterus, and also into nsevi. 
The hypodermic injection of these salts causes some pain and swelling, but 
no further symptoms follow, and the iron is found for the most part deposited 
in an insoluble form at the point of injection. 

The General Symptoms of iron are obtained only by the intravenous in- 
jection of double salts, such as the tartrate of iron and sodium, which do not 
coagulate the blood, and at the same time are capable of freeing the iron 
ion in the tissues. Such salts as the ferrocyanides or ferricyanides on the 
other hand leave the body as such, and the iron ion is not liberated, so that 
no iron symptoms are induced. Meyer and Williams found that the double 
tartrate caused in the frog slowness and clumsiness in movement, which 
gradually developed into complete paralysis of the central nervous system. 
The heart seemed to be little affected, but the skeletal muscles were some- 
what less irritable than usual after death. In mammals, the symptoms of 
iron poisoning were often very late in appearing, and began with some 
acceleration of the breathing, which later became slow T and dyspnceic ; 
vomiting and diarrhoea often followed, and blood was sometimes seen in the 
evacuations of the stomach and bowel. Increasing weakness was followed 
by central paralysis and death, accompanied by weak convulsive movements. 
The heart seemed little affected, although the blood-pressure fell rapidly 
towards the end. Post-mortem, the mucous membranes of the stomach and 
intestine were found swollen and congested, and often contained numerous 
small blood extravasations. Robert found that repeated injection of small 
quantities of the citrate of iron induces congestion of the kidney and the ap- 
pearance of casts and albumin in the urine. In acute poisoning the alka- 
linity of the blood is reduced owing to the excess of lactic acid formed. 

Iron, like the other heavy metals, would therefore seem to have a specific 
irritant effect on the intestinal and gastric mucous membrane, and to a less 
extent on the kidney. In addition, it depresses and eventually paralyzes 
the central nervous system, but it is impossible to state how far this is due 
to direct action, and 'how far it is secondary to the action in the alimentary 
canal. 

According to Robert, iron perfused through the vessels has no effect on 
their calibre except in large doses, when it dilates them. The astringent 
action is due, therefore, to the precipitation of the proteids, and not to con- 
striction of the vessels. 

Apart from irritation of the stomach and intestine, no symptoms are 
induced by iron given by the mouth, because it is absorbed too slowly and 
in too small amount, and perhaps in a form which has little tendency to 
cause them. 

The Absorption of Iron has been a subject of discussion only during 
the latter half of the last century, for up to that time it had been assumed 
that it passed into the tissues witli comparative ease, ami was there 



662 ' THE HEAVY METALS. 

formed to haemoglobin. In this way was explained its effect in 
anaemia, particularly in the form known as chlorosis, in which there is 
a deficiency of haemoglobin rather than of blood cells. The benefit 
accruing from the use of iron salts in this disease has been attested by 
so many generations of physicians that only the most skeptical can 
have any doubt on the subject. The first to question this explanation 
of the action of iron in chlorosis was Kletzinsky, who formulated a 
theory of its action, which was soon forgotten, however, and only 
became popularly known when it was resuscitated by Bunge. This 
explanation, which is generally stated as Bunge's theory, has been 
widely held during the last few years, but has now been abandoned by 
almost all its former supporters including its author, who has been 
compelled to admit not only that iron salts are absorbed but that their 
administration leads to an increased formation of haemoglobin. 

No account of the action of iron would be complete, however, without 
reference to an explanation, which has at least had the effect of establishing 
a number of facts regarding the fate of iron in the body, and also the less 
desirable result of increasing to a considerable extent the number of pat- 
ented preparations containing iron. Shortly stated, Bunge's theory is that 
in ordinary conditions a certain amount of iron is lost by the body constantly 
through the excretions, and this loss is made up by the absorption of the iron 
contained in the food. This food-iron consists wholly of organic iron, that 
is, of iron combined in such a way that sulphides attack it with difficulty ; 
an example of such organic iron is the haematogen of the yolk of egg. In 
normal individuals the food-iron is sufficient to replace that lost by excre- 
tion, but in chlorosis the presence of large amounts of sulphides in the in- 
testine causes the food-irons to be decomposed to ferric sulphide, which is 
insoluble and unabsorbable. When the ordinary inorganic iron prepara- 
tions are administered in these cases, they are not taken up in place of 
the food-irons ; but, by forming sulphide in the intestine, they remove the 
sulphuretted hydrogen, and prevent the decomposition of the food-irons, 
which thus remain capable of being absorbed. Bunge and his followers 
went on to state that inorganic iron is never under any circumstances ab- 
sorbed by the normal epithelium, but that when large quantities are admin- 
istered, they tend to corrode the walls of the stomach and intestine, and are 
thus absorbed to some extent. Even then, however, they are ineapable of 
being formed to haemoglobin, the animal body being able to perform only 
the last steps of this synthesis, after the plants have formed the simpler 
types of organic iron. This theory now possesses only historical interest, so 
that it is unnecessary to enumerate the arguments brought against it. It 
may be sufficient to state that if the ordinary preparations of iron acted only 
by binding the sulphides of the intestine, various other metals would be 
equally efficient in chlorosis ; iron would not be beneficial injected hypoder- 
mically, and iron sulphide given so as to escape the action of the gastric 
juice would be equally useless. It is found, however, that no other metal 
can replace iron in chlorosis ; that iron injected hypodermically is curative 
in chlorosis, and that the sulphide administered so as to reach the intestine 
unchanged, acts as well as other preparations (Stockman). Finally, it has 
been shown that ordinary preparations of iron are absorbed. The same 
arguments may be brought against two other theories which have been pro- 
posed to explain the action of iron in chlorosis without absorption. In the 
first of these it is supposed that in chlorosis the mucus of the intestine is 
increased and prevents the absorption of the food-iron, while the inorganic 
iron precipitates the mucus and thus removes it. The other is that the inor- 
ganic iron acts as a carminative, increases the circulation in the intestine, 



IRON. 663 

and thus promotes the absorption of food-iron. It may be remarked in 
passing that there is no reason to suppose that the sulphides or mucus of 
the intestine are increased in chlorosis, or that its circulation is so weak as 
to prevent absorption. 

Driven from their former position that inorganic iron is not absorbed by 
the intestine, the advocates of the use of organic iron in chlorosis have at- 
tempted to make a further stand by asserting that, although the ordinary 
preparations are absorbed, they are not used in the formation of haemoglobin, 
but after a more or less prolonged stay in the liver and other organs, are 
excreted. This statement is refuted, however, by several researches, in 
which the addition of inorganic iron to food deficient in iron (milk), or 
entirely free from it, prevented the anaemia which was observed in animals 
fed on the same food, but without iron. Finally Abderhalden, the latest ex- 
ponent of Bunge's views, finds that inorganic iron increases the haemoglobin 
of the blood, but suggests that it may do so indirectly by taking the place of 
the food-iron which supplies the needs of the tissues, the food-iron then being 
formed to haemoglobin ; he fails to supply any arguments in support of this 
theory, which it is therefore unnecessary to discuss. 

The chief difficulties in following the course of iron in the body are 
due to its being present in all the tissues and secretions normally, and 
to the very small quantity which is contained in ordinary food, and 
which is essential to the maintenance of health. About 2J-3J G. 
(40-55 grs.) of iron are estimated to be present in the tissues of a 
healthy human adult, the greater part of it existing in the form of 
haemoglobin in the blood. Formerly it was believed that some 50 
mgs. (1 gr.) of iron were taken in the food per day, but Stockman and 
Greig have recently shown that this estimate is much too high, and 
that an ordinary dietary provides only about 5-10 mgs. (-j 1 ^— § gr.) of 
iron per day ; they found in one case that even 3-5 mgs. ( a 1 o "*iV & r ') 
were sufficient to preserve the iron equilibrium. About the same 
amount of iron is excreted per day, chiefly in the faeces, to a much 
smaller extent in the urine. 

When additional iron is supplied to the body, either as inorganic or 
as organic iron, much the greater part of it reappears in the stools. 
This does not necessarily entail that all of it has passed through the 
bowel unabsorbed, for it is now perfectly certain that iron is excreted 
through the intestinal epithelium, so that some of the iron of the stools 
may have been absorbed and reexcreted. The strongest argument cited 
by Bunge in support of his theory was that inorganic iron, given by 
the mouth, did not increase the iron of the urine. He assumed that 
any iron absorbed would necessarily appear in course of time in the 
urine, but this has been shown to be incorrect by a whole series of in- 
vestigations. When iron salts such as the double tartrate are injected 
into a vein, they soon disappear from the blood, but only some 2-5 
per cent, of the quantity injected reappears in the urine, the rest being 
withdrawn from the blood and stored up in the cells of the liver and 
spleen, and perhaps in the bone-marrow. Thus even if iron i< ab- 
sorbed in the intestine, it is improbable that it will reappear in the 
urine in appreciable quantity, for supposing 10 mgs. to be taken up, 2 
per cent, of this would represent only \ mg. and this lies within the 
limits of error of estimation. In addition, it seems probable that when 



004 THE HEA VY METALS. 

iron enters the blood slowly and in small quantities, even a less pro- 
portion of it is excreted in the urine than when larger quantities are 
injected suddenly. At any rate, the ordinary preparations of iron 
when given by the mouth do not increase the iron of the urine, while 
the results of the different investigators differ in regard to organic 
iron, for some have found it increase the urinary iron, while other and 
perhaps more impartial investigators have found it unaffected. On 
the whole the evidence goes to show that 0.5—1.5 mgs. of iron are 
normally excreted in the urine in 24 hours, and that the administra- 
tion per os of iron preparations, whether organic or inorganic, does 
not affect this amount. The fact that an iron preparation given by the 
mouth does not increase the iron in the urine, is therefore no evidence 
that it has not been absorbed from the stomach. 

Iron injected into the veins of normal animals is stored up in the 
liver and spleen, but is slowly taken up from these organs again, and 
is excreted by the epithelium of the caecum and colon. When iron is 
given by the mouth, therefore, it may either pass along the canal and 
be thrown out in the faeces, or it may be absorbed, make a stay in the 
liver, be excreted in the large intestine, and again appear in the stools. 
The comparison of the iron in the food and in drugs with that of the 
stools therefore gives no clue as to how much has been absorbed, and 
how much has simply passed through the intestine. 

But the passage of iron from the liver to the intestine is a somewhat 
slow T process, and it is therefore possible to detect the excess of iron in 
the liver. This has been done repeatedly by the following method. 
Young animals of the same litter fed on milk have approximately the 
same amount of iron in the liver. If one be fed on milk only, the 
other on milk to which iron is added, the liver of the latter is found 
to contain more iron than that of the control. Other investigators 
have fed animals (rats or mice) on food that is practically free from 
iron, have killed them and estimated the iron in the whole body apart 
from the alimentary tract and compared it with that of animals treated 
in the same way except that iron was added to the food. The latter 
group contains much more iron than the control group fed on iron-free 
food, and in general presents a much more healthy and normal ap- 
pearance. 

Finally, attempts have been made to follow the iron in its course 
through the tissues. This is possible by the histological examination 
of tissues soaked in ammonium sulphide solution, in potassic ferrocy- 
anide and hydrochloric acid, or in hematoxylin, as these form black 
or blue precipitates with most forms of iron, but leave the haemoglobin 
unaffected. When animals are given iron preparations, and are then 
killed, and their organs stained by these reagents, the mucous mem- 
brane of the stomach and of the greater part of the small intestine gives 
no coloration, but the epithelium of the duodenum and the upper part 
of the jejunum is found to contain numerous granules of iron. These 
granules may be traced to the mesenteric lymph glands, are found in 
large numbers in the spleen around the corpuscles, to a much smaller 



IRON. 065 

extent in the liver, and in the cortex of the kidney. If, however, the 
animal be kept for some days after the iron is given, the reaction in 
the duodenum, spleen, and mesenteric glands is less intense, while the 
liver gives much more distinct evidence of containing iron, and the 
epithelial cells of the large intestine and caecum also give a strong 
reaction. This is interpreted to mean that iron is absorbed by the 
duodenum and is first stored in the spleen, but later finds its way 
through the blood vessels to the liver, where it rests again for some 
time, to be eventually taken up again by the blood and excreted into 
the large intestine and the caecum. There is some question as to 
whether the lymph vessels are involved in the absorption of iron and 
the most recent investigators have failed to find it in the thoracic duct 
and accordingly hold that it is absorbed from the intestine into the 
blood vessels directly. The iron stored in the liver does not escape 
by the bile as might be anticipated. A small percentage of iron is a 
constant constituent of this fluid, but is not increased by iron given by 
the mouth or intravenously. 

Nothing is known with certainty regarding the form in which iron 
is absorbed. It is assumed that in the stomach almost all the prepa- 
rations form chlorides to a greater or less extent, 1 are then changed 
into albuminates, and in this form pass into the duodenum, where they 
may be absorbed in solution, or may be precipitated and taken up as 
solids by the epithelial cells and the leucocytes. In the liver it seems 
likely that the absorbed iron is changed to hepatic ferratin, and that it 
is stored in this form. Several other iron compounds have been found 
in the liver, and iron undoubtedly undergoes a number of synthetic 
processes there. 

It must not be inferred from the foregoing that all of the inorganic 
iron swallowed is taken up by the intestinal epithelium. It is quite 
impossible to form even approximate estimates of the amount that is 
really absorbed and made use of by the tissues, but the probability 
is that only a small percentage is really taken up ; the rest passing 
through the intestine and being thrown out in the stools. It is often 
stated that the iron stools are dark or black in color, from the sulphide 
present, but this seems to be seldom the case when they are passed, 
although they assume a darker gray or grayish black color in the air 
from oxidation. The iron is contained in them only to a small extent 
as the sulphide, some of the rest probably being albuminate. 

To sum up what is known regarding the fate of the iron preparations, 
they are partially formed to the chloride and then to the albuminate in 
the stomach, pass into the duodenum, from which the great bulk is car- 
ried on into the lower parts of the intestine, while some is absorbed by 
the epithelium and leucocytes in solid form and perhaps in solution. 
It is then deposited in the spleen, where it may undergo some changes 
in form, is later taken up by the blood and deposited in the liver and 
perhaps in the bone marrow. Where the supply of iron has been 

1 According to several of the older authors the ferric salts are changed to ferrous in 
the stomach. 



666 THE HE A VY METALS. 

inadequate for the formation of haemoglobin, the originally inorganic 
iron is probably worked into higher forms and eventually into haemo- 
globin in the liver, and it seems likely that ferratin is one of the 
intermediate steps in this synthesis. When there is no deficiency of 
iron for the formation of haemoglobin, the liver slowly yields its store 
of iron to the blood, which carries it to the caecum and large intestine, 
by the epithelium of which it is finally excreted. It is to be noted 
that the iron absorbed does not increase the amount of iron in the 
urine, bile or other excretions. The investigations on which this sketch 
is founded have been completed only in the last few years, and establish 
finally the truth of the position held by the older physicians and indeed 
by the clinicians of this later time also, that inorganic iron follows the 
same course in the tissues as food- iron, although possibly more of the 
latter is absorbed. 

But this explanation of the iron action does not cover all the diffi- 
culties of the case. Many cases of chlorosis recover without inorganic 
iron under hygienic conditions, such as rest, and particularly when 
foods rich in iron are prescribed, this being exactly what is to be ex- 
pected on the theory that inorganic iron merely takes the place of the 
deficient food-iron. But many chlorotic patients show little or no 
improvement when treated with foods containing iron, even when there 
is no question that the iron supplied daily in food form is sufficient for 
the needs of the economy, and chlorosis even appears in individuals 
who have never suffered from any deficiency of food-iron. Yet many 
of these cases recover rapidly under inorganic iron. V. Noorden has 
attempted to explain this by supposing that inorganic iron when 
absorbed acts as a stimulant to the blood-forming organs, while food- 
iron has no such property. And some indications of abnormal activity 
of the bone-marrow cells have been observed in animals supplied with 
inorganic iron ; this may not be the effect of stimulation in the ordi- 
nary sense of the word, however, for it may be explained by the un- 
usual abundance of the materials necessary to their activity. The 
difference in the effects of the irons of the food and of the inorganic 
preparations may be due to the fact that food-iron is always accom- 
panied by a large amount of colloid material, which may materially 
delay its absorption while inorganic iron on the other hand is much 
less completely enveloped, and may be more easily absorbed. In ad- 
dition, the iron preparations are given in much larger amounts than 
the food-irons. When 10 mgs. (food-iron) are taken per day, only a 
small proportion (e. g., 5 mgs.) may be absorbed, and this may be 
insufficient to supply the needs of the body, but if some hundreds of 
milligrams of inorganic iron be added, the proportion absorbed will be 
amply sufficient. The same effect might be obtained by the same 
amount of food-iron, but this is only to be obtained by giving more 
food than can be digested. 

Iron is not absorbed from the unbroken skin, and the iron and steel 
baths are therefore of no value in themselves in the treatment of 
anaemia. 



IRON. 667 

Therapeutic Uses. — Iron is most frequently used in the treatment of 
Chlorosis, which in a large proportion of cases recovers entirely under 
it. Some cases, however, improve somewhat under iron, but relapse 
when it is left off, and a certain number of patients show no improve- 
ment whatever under it. These last are not generally regarded as 
suffering from chlorosis proper, but from a more malignant form of 
anaemia. A number of symptoms which are due to chlorosis, and 
which are often more prominent than the original disease, are also re- 
lieved or entirely removed by iron. Thus gastric catarrh, arnenorrhcea, 
or oedema may disappear under it, but in these cases the symptoms 
are chlorotic in origin, and the improvement is due to the increased 
haemoglobin, and not to the direct action of iron on the stomach, uterus 
or circulation. In chlorosis, the iron is generally given in small doses, 
at any rate at first, and the less astringent preparations are preferred 
by most clinicians, although some still advise the perchloride. When 
chlorosis is complicated with gastric catarrh, some authorities advise 
that the latter be treated before the general condition, as iron in itself 
is liable to irritate the stomach. In many cases, however, the catarrh 
is secondary to the chlorosis, and can only be treated successfully by 
improving the condition of the blood ; the iron preparation here ought 
to be mild and not irritating. In chlorosis the tendency to constipa- 
tion may be increased by iron, and a purge is often required, such as 
the iron and aloes pill, which is particularly recommended when chlo- 
rosis is attended by arnenorrhcea. 

Iron is of less value in other forms of anaemia, although it is often 
prescribed and may be followed by some improvement. Thus it may 
be administered during convalescence from acute disease, such as 
typhoid fever, or nephritis, and in the anaemia induced by profuse 
haemorrhage, iron often seems to accelerate the recuperation of the 
blood. It is often prescribed for the cachexia of malaria, syphilis and 
other chronic diseases. 

Iron is said to be contraindicated where there is fever, in plethoric 
individuals with a tendency to haemorrhages, and in some forms of 
heart disease. In these conditions the iron preparations can harm 
only from a reflex induced from the stomach, as the small quantity of 
iron absorbed is incapable of producing any effects in the tissues. In 
phthisis, it is very generally credited with causing haemorrhage from 
the lungs, but it may be questioned how far this apprehension is based 
on observation, and how far it is a relic of old and forgotten theories 
of the action of iron. It has to be given with caution here in order 
to avoid irritation of the stomach and dyspepsia, and in the presence 
of gastric catarrh from any cause, its effects have to be watched care- 
fully. 

Some of the older authorities advise iron to be given in large quan- 
tities, but the dose has been reduced of late 1 years to about 0.1-0.2 
G. (2-3 grs.) three times a day. It is given after meals in order t«> 
avoid the irritant action on the stomach as far as possible. It Is to be 
noted that on giving 0.1 G. of iron three times a day, about thirty 



6G8 THE HE A VY METALS. 

times as much iron is given as is required normally in food, so that 
the chlorotic receives more iron per day than a workman in a month. 

Iron is occasionally injected hypodermically, with the object of 
avoiding the irritation of the stomach, but this procedure is painful 
and causes some swelling and irritation, which lasts twenty-four hours 
or more. Most of the salts are precipitated at the point of injection, 
but some, such as the citrate, are taken up by the blood at once ; the 
danger of renal irritation, anticipated by Kobert, does not seem to 
arise if small quantities are used. The citrate and pyro-phosphate in 
5 per cent, solution have been used in this way, 0.05-0.1 G. (1-2 grs.) 
of the salt being injected daily. The hydrate and oxide have also 
been injected, suspended in salt solution, but are somewhat more irri- 
tant, while the peptonate is recommended as being almost devoid of 
irritant qualities. 

Iron has been recommended in erysipelas, but has proved valueless 
in the hands of most investigators. Some of the iron salts are employed 
as Astringents, the most popular preparations for this purpose being the 
ferrous sulphate, which has been used to some extent in diarrhoea, and 
also externally. The perchloride is perhaps the best Styptic of its 
class. When applied to a bleeding point, it precipitates the proteids of 
the blood plasma, and thus forms an obstruction to the flow of blood 
similar to that caused by clotting, although no fibrin, but only a mass 
of iron albuminate, is formed by the perchloride. This styptic action 
is of value in capillary and recurrent haemorrhage, while in bleed- 
ing from an artery, the ordinary surgical methods are of course pre- 
ferred. The chloride arrests haemorrhage only when it can be brought 
into actual contact with the bleeding point, and where this is covered 
by a large mass of semicoagulated blood, the treatment is of no avail, 
as it simply forms the albuminate with the blood with which it comes 
into contact first, and this may be far from the actual point of rupture. 
As an application to the stomach and bowel in haemorrhage from these 
parts, the perchloride is unlikely to prove successful, while in bleed- 
ing from the nose, or gums, or after the extraction of a tooth, it is 
more reliable. It has been injected into the uterus in haemorrhage, 
into naevus in order to cause coagulation and subsequent cicatrization 
of the tissue, and into aneurisms. This is a very dangerous treat- 
ment, however, for several cases of fatal embolism have arisen from 
the precipitated albuminate being carried off in the veins. Perchloride 
of iron solution has been sprayed into the air passages in haemoptysis, 
but if sufficiently concentrated to coagulate the blood at the bleeding 
point in the lungs, it would certainly induce irritation and coughing. 
The perchloride is, of course, valueless in haemorrhage from internal 
organs, for in the first place, very little of it is absorbed, and in the 
second place, what does pass into the tissues is already in proteid com- 
bination, and therefore incapable of coagulating the blood. The same 
objection applies to the alleged astringent effect of iron in nephritis. 
It is possible that iron may lessen the albumin in the urine in these 
cases, although the clinical evidence is contradictory on the subject, 



IRON. 

but it is absolutely certain that it does not do so by any local action 
on the albumin in the kidney. 

The sulphate of iron is used as a disinfectant for sewage. It acts 
here merely by precipitating the proteids, which carry down the bac- 
teria mechanically. The proteids of the sewage may be increased by 
the addition of blood before the sulphate is applied. The sulphate of 
iron is used, because it is cheaper than the other salts of the heavy 
metals. 

Preparations. 

Ferri Chloridum (U. S. P.), ferric chloride (Fe 2 Cl 6 -f-12H 2 0), orange yellow 
crystals, with a strong astringent taste, very deliquescent in air, soluble in 
water and alcohol. 

Liquor Ferri Chloridi (U. S. P.), a solution of ferric chloride containing 
about 37.8 per cent, of the anhydrous salt or about 13 per cent, of iron. 

Tinctura Ferri Chloridi (U. S. P.) is formed from the liquor by dilut- 
ing it with 3 parts of alcohol. 0.5-2 c.c. (8-30 mins.). 

Liquor Ferri Perchloridi Fortis (B. P.) is formed by dissolving iron in hy- 
drochloric acid, and contains 22J per cent, of iron. It is an orange-brown 
fluid, with a strong astringent taste. 

Liquor Ferri Perchloridi (B. P.) and 

Tinctura Ferri Perchloridi (B. P.) are formed by diluting the strong 
liquor with 3 times as much water, and with two parts of water and one of 
alcohol respectively. 5-15 mins. 

The chloride is used as a styptic either as the Liquor Fortis (B. P.) or in a 
very much stronger form, prepared by allowing the crystals to deliquesce. 
A plug of cotton-wool steeped in the solution is used to stop bleeding after 
the extraction of teeth, and the liquor has been injected into the uterus in 
haemorrhage, and into aneurisms and nsevi. When diluted it may be used 
as a gargle, but has a disagreeable, inky taste, and attacks the teeth. The 
tincture is very commonly used in the treatment of chlorosis. It ought to be 
taken in a glass of water, and through a quill or glass tube, in order to avoid 
injury to the teeth. 

Liquor Ferri Nitratis (IT. S. P.), an aqueous solution of ferric nitrate 
(Fe 2 (N0 3 ) 6 ), containing about 6.2 per cent, of the anhydrous salt and about 
1.4 per cent, of metallic iron. 1-2 c.c. (15-30 mins.). 

Liquor Ferri Nitratis (B. P.) contains 3.3 per cent, of iron. 5-15 mins. 
Used as an astringent to a limited extent. 

Liquor Ferri Tersulphatis (U. S. P.), Liquor Ferri PersuJphatis (B. P.), 
lution of ferric sulphate (Fe 2 (S0 4 ) 3 ), is used only for the preparation of other 
iron salts. 

Liquor Ferri Subsulphatis (U. S. P.), Monsel's solution, an aqueous solu- 
tion of basic ferric sulphate of variable chemical composition, and containing 
about 13.8 per cent, of metallic iron. 0.2-0.6 c.c. (3-10 mins. }. (Jsed as an 
astringent gargle, and in general like the chloride. 

Ferri Sulphas (U. S. P., B. P.), ferrous sulphate (FeSO, 7H.O), large, 
pale, bluish-green crystals with a saline, astringent taste, soluble in water, 
insoluble in alcohol, and unstable in moist air. 0.05-0.3 G. (1-5 grs.). 

Ferri Sulphas Granulatus (U. S. P.), recrystallized ferrous sulphate in very 
small crystals. 0.05-0.3 G. (1-5 grs.). 

Ferri Sulphas Exsiccatus (U. S. P., B. P.), dried ferrous Bulphat* 2F< - I 
+ 3H 2 0), ordinary sulphate from which most of the water of crystal lizatioD 
has been driven off by heat. A grayish-white powder resembling the ordi 
nary sulphate in its solubility. 0.03-0.2 G grs.). 

Ferri et Ammonii Sulphas (U. S. V.), ammonio ferric sulphate or amnionio- 
ferric alum (Fe 2 (NHJ 2 (SOJ. t +24H 2 0), is a double salt forming pale violet 



6 70 THE HE A VY METALS. 

crystals with an acid astringent taste — soluble in water, not in alcohol 
0.3-0.6 G. (5-10 grs.). 

The sulphate of iron is very astringent, though less so than the ferric salts. 
It is used as an astringent application to mucous membranes, such as the 
eye," mouth, urethra, more rarely internally in anajmia, although it is less 
irritant than the chloride. 

The Pil. Aloes et Ferri (U. S. P., B. P.), which is used very largely in 
amenorrhoea and in chlorosis with constipation, contains dried sulphate of 
iron. Dose, B. P., 4-8 grs. 

Ferrum (U. S. P., B. P.), metallic iron in the shape of fine wire is used only 
to form other preparations. 

Ferrum Reductum (U. S. P.), Ferrum Redactum (B. P.), reduced iron, 
a very fine grayish-black, lustreless powder, without taste, insoluble in water 
or alcohol, soluble in acid. It consists of metallic iron, with a small amount 
of the magnetic oxide. 0.05-0.3 G. (1-5 grs.). 

Trochiscus Ferri Redacti (B. P.), each contains 1 gr. of reduced iron. 

Ferri Carbonas Saccharatus (U. S. P., B. P.), saccharated ferrous car- 
bonate, is formed by precipitating ferrous sulphate with sodium bicarbonate 
(ammonium carbonate, B. P.), washing the precipitate and adding sugar. It 
contains ferrous carbonate along with some ferrous sulphate and sodium bi- 
carbonate (U. S. P.), and is a greenish-brown powder, which rapidly oxidizes 
in the air, and has a sweetish, astringent taste. The carbonate is a very 
unstable body, and on keeping is slowly transformed to ferric hydrate 
(Fe 2 (OH) 6 ). The sugar is added in order to retard this oxidation, but the 
carbonate ought not to be dispensed unless it is of recent preparation. 0.6- 
2G. (10-30 grs.). 

Pilule Ferri Carbonatis (U. S. P.), Pilula Ferri (B. P.), ferruginous 
or chalybeate pills, blaud's pills, are prepared in the same way, by the ac- 
tion of ferrous sulphate and carbonate of potash or soda. Sugar, tragacanth 
and glycerin are added ; they ought to be freshly prepared in order to avoid 
the formation of the hydrate. Each pill (U. S. P.) contains about 0.06 G. 
(1 gr.) of iron, that is, 5 grs. contain about 1 gr. A method of keeping the 
carbonate and the sulphate apart until actually swallowed has been adver- 
tised, the two being given in a capsule, but being separated by a membrane 
which is dissolved off in the stomach. This same effect would be obtained by 
giving them entirely separate, and it is extremely improbable that the car- 
bonate is formed in the acid contents of the stomach. 1-5 pills U. S. P., 5- 
15 grs. B. P. 

Massa Ferri Carbonatis (U. S. P.), Vallets' Mass, is formed by the action 
of ferrous sulphate and sodium carbonate. Sugar and honey are added to 
the precipitate to form a mass of the proper consistency for pills. This 
preparation has never enjoyed the popularity of Blaud's pills and is super- 
fluous. 0.2-0 3 G. (3-5 grs.). 

Mistura Ferri Composita (IT. S. P., B. P.), Griffith's mixture, is formed 
by mixing ferrous sulphate, potassium carbonate, myrrh, sugar, spirits of 
lavender (nutmeg, B. P.) and rose water. The ferrous carbonate (FeC0 3 ) is 
precipitated and the mixture has therefore to be shaken before taking, and 
ought to be freshly prepared. 15-30 c.c. Q-l fl. dr.). 

Reduced iron and the four carbonate preparations are used exclusively in 
the treatment of anaemia. They are practically devoid of irritant properties, 
and are among the best of all the iron preparations for this purpose. The 
Blaud's Pills have in particular a well merited reputation in the treatment 
of chlorosis and of chlorotic amenorrhoea. Another preparation used for 
this purpose but not official is Ferrum Diahjsatum in which a considerable 
amount of iron oxide is kept in a semi-colloid state dissolved in a minimum 
amount of the chloride. It tastes of iron but is not astringent. 

Ferri Oxidum Hydratum (U. S. P.), ferric hydrate, or hydroxide 
(Fe 2 (OH) fi \ a brownish-red, pasty mass, insoluble in water or alcohol but 
soluble in hydrochloric acid, is used almost exclusively in the treatment of 



IRON. 671 

arsenic poisoning, as it forms an insoluble compound with it in the stomach. 
It ought to be freshly prepared, as otherwise it forms particles which com- 
bine with greater difficulty with the poison. 

Ferri Oxidum Hydratum cum Magnesia (U. S. P.) is formed by precipitating 
ferric sulphate by magnesia and is used in arsenic poisoning and known 
as the arsenic antidote. Both of those preparations have to be given freely 
in arsenic poisoning, at least 15-20 G. {\ oz.). The remedy is harmless in 
itself. 

Emplastrum Ferri (IT. S. P.) and Trochisci Ferri (II. S. P.), iron plaster 
and iron lozenges, are prepared from ferric hydrate, but are not used in 
practice. The plaster has no effect except that of giving mechanical sup- 
port, as iron is not absorbed by the skin. 

Liquor Ferri Acetatis (U. S. P., B. P.), an aqueous solution of the acetate 
(Fe 2 (C 2 H 3 2 ) 6 ), containing about 31 per cent, of the salt or about 7.5 per 
cent, of iron. 0.3-1 c.c. (5-15 mins). 

Ferri Valerianas (U. S. P.), ferric valerianate, a dark, brick-red, amor- 
phous powder, having the odor of valerianic acid and a mild, astringent 
taste, insoluble in water, soluble in alcohol. 0.05-0.3 G. (1-5 grs.). 

Ferri Lactas (U. S. P.), ferrous lactate (Fe(C 3 H 5 3 ) 2 -f 3H 2 0), pale, green- 
ish crusts, having a slight odor and a mildly astringent taste, soluble in 40 
parts of water, more so in alkali citrate solutions, insoluble in alcohol. 
0.05-0.3 G. (1-5 grs.). 

The lactate is contained in the Syrupus Hypophosphitum cum Ferro (U. S. P.), 
2-4 c.c. (i-1 fl. oz.). 

Ferri Citras (U. S. P.), transparent, garnet-red scales with a slight iron 
taste. 0.05-0.3 G. (1-5 grs.). 

Liquor Ferri Citratis (U. S. P.), an aqueous solution containing about 7£ 
percent, of iron. 0.3-1 c.c. (5-15 mins.). 

Ferri Phosphas (B. P.), a powder containing not less than 47 per cent, of hy- 
drous ferrous phosphate (Fe 3 (P0 4 ) 2 8H 2 0), with ferric phosphate and some iron 
oxide. It is a slate-blue, amorphous powder, insoluble in water. 5-10 grs. 

Syrupus Ferri Phosphatis (B. P.). 1 fl. dr. represents 1 gr. of anhydrous 
ferrous phosphate. ^-1 fl. dr. 

Ferri Phosphas Solubilis (U. S. P.). The phosphate of iron is insoluble in 
itself, but is rendered soluble by the presence of sodium citrate — thin, green 
scales with a saline taste, insoluble in alcohol. 0.1-0.5 G. (2-8 grs.). 

Ferri Pyrophosphas Solubilis (U. S. P.), like the phosphate, is rendered 
soluble by sodium citrate, and resembles it in its appearance and solubility. 
0.1-0.5 G. (2-8 grs.). 

Ferri Hypophosphis (U. S. P.) (Fe 2 (PH 2 2 ) fi ), a white powder, odorless 
and nearly tasteless, almost insoluble in water, but dissolved by solutions of 
the alkali citrates. 0.3-1 G. (5-15 grs.), in pill. 

Ferri Iodidum Saccharatum (U. S. P.), saccharated ferrous iodide a yel- 
lowish-white, very hygroscopic powder with a sweetish, iron taste, soluble 
in water, less so in alcohol. 0.1-0.3 G. (2-5 grs.). 

Pilulss Ferri Iodidi (U. S. P.), each contains 0.04 G. of iron. 1-2 pills. 

Syrupus Ferri Iodidi (U. S. P., B. P.) contains about l.S per cent, of iron. 
2-4 G. Q-l fl. dr.). 

Ferri Arsenas (B. P.), iron arsenate, consists of ferrous arsenate 
(Fe 3 (As0 4 ) 2 , 6H 2 0), with ferric arsenate and some iron oxide, and forma a 
tasteless, amorphous powder of a greenish color, insoluble in water. ,'. - 1 gr. 

These preparations have all been prescribed to a greater or less extent in 
the treatment of anaemia, the lactate, phosphate and pyrophosphate being 
perhaps more widely used than the others. It is needless to repeal that the 
valerianate is not of greater value in hysteria than the other preparations, as 
valerianic acid is useless in this condition. The iodide has been advised in 
order to combine the effects of iodide and iron, hut the iodide given in this 
form is in much smaller quantity than that found necessary in the iodide ^\' 
potassium treatment, and it seems open to question whether the improvement 



072 THE HEAVY METALS. 

is not due to the iron only. The hypophosphite is also used in cachexia, in 
order to combine the hypophosphite and the iron effects. 

Ferri et Quininie Citras (U. 8. P., B. P.), thin scales of a reddish-brown 
color, and of a bitter, iron taste, slowly soluble in water, partially soluble in 
alcohol, containing 11.5 percent, of quinine and 14. 5 per cent, of iron U. B. P. 
0.3-0.6 G. (5-10 grs.). 

Ferri et Quinines Citras Solubilis (U. S. P.), thin scales of a greenish color 
and of a bitter, iron taste, easily soluble in water, only partially in alcohol. 
It contains the same amount of iron and quinine as the ordinary preparation. 
0.3-0.6 G. (5-10 grs.). 

Ferri et Strychnines Citras (U. S. P.), thin, transparent scales of garnet-red 
or yellowish-brown color, readily soluble in water, containing about 1 per 
cent, of strychnine and about 16 per cent, of iron. 0.1-0.3 G. (2-5 grs.). 

Syrupus Ferri, Quininse et Strychnine Phosphatum (U. S. P.), Syrupus Ferri 
Fhosphatis cum Quinina et Strychnina (B. P.), 2-4 c.c. (£-1 fl. dr.). 

Ferri et Ammonii Citras (U. S. P., B. P.), thin garnet-red scales with an 
acid, iron taste, soluble in water and containing 16 per cent. iron. 0.3-0.6 
G. (5-10 grs.). 

Ferri et Ammonii Tartras (U. S. P.), thin, transparent, garnet-red scales, 
very soluble in water and containing about 17 per cent, of iron. 0.3-0.6 G. 
(5-10 grs.). 

Ferri et Potassii Tartras (U. S. P.), Ferrum Tartaratum (B. P.) resembles the 
last preparation, but contains only about 15 per cent, of iron. 0.3-0.6 G. 
(5-10 grs.). 

Liquor Ferri et Ammonii Acetatis (U. S. P.), Basham's mixture, contains 
only a very small proportion of iron, along with acetic acid, ammonium 
acetate, aromatic elixir and glycerin. 15-30 c.c. (£-1 fl. oz.). 

Vinum Ferri (B. P.). 1-4 fl. drs. 

Vinum Ferri Amarum (U. S. P.). 8-15 c.c. (2-4 fl. drs.). 

Vinum Ferri Citratis (U. S. P., B. P.). 4-15 c.c. (1-4 fl. drs.). 

The two wines of iron of the U. S. P. are practically identical except that 
the first contains the citrate of iron and quinine, the second, the citrate of 
iron and ammonium. Each is made up with tincture of sweet orange peel, 
syrup and white wine. The iron wine of the B. P. is formed by dissolving 
iron in sherry wine, the citrate of iron wine by dissolving the citrate in 
orange wine. 

The double salts of iron (scale preparations) and the wines are used to 
some extent in chlorosis, but more frequently in convalescence from acute 
fevers, which is often attended by anaemia : in these cases the iron wines 
are often of considerable value. The double salts are not so liable to disturb 
the digestion as the other soluble preparations of iron, but are not superior 
to the carbonate preparations and the reduced iron in this respect. 

Iron is contained in many mineral waters, which are therefore advised in 
cases of anaemia. It is generally in the form of the carbonate, which is dis- 
solved by the excess of carbonic acid present, but becomes oxidized to 
the insoluble ferric hydrate in the air. The amount of iron contained is 
small, seldom being more than 0.1 G. per litre, but the treatment of 
chlorosis is unquestionably aided by change of scene and in particular by the 
high elevations at which many of these springs are situated, so that the suc- 
cess of treatment with these iron waters is perfectly intelligible. Bathing in 
iron water has no further action on the blood than ordinary baths, as no 
iron is absorbed. 

Many Proteid Compounds of iron have been introduced into therapeutics 
in the last few years, but few of them need be mentioned, as a large number 
of them promise to be relegated to merited oblivion in the near future. The 
albuminate of iron and the peptonate of iron are generally prepared by the 
action of the chloride on egg albumin or on peptone, and differ very consid- 
erably in the percentage of iron contained. In most of them the albu- 
minate or peptonate is accompanied by more or less perchloride and oxide. 



IRON. 673 

These preparations are not "organic " iron in the sense defined on page 669, 
for the iron can be split off easily, and is precipitated by sulphides almost 
as readily as the ordinary salts. The albuminate and peptonate possess no 
advantage over the usual preparations, unless they prove less irritant to the 
stomach, and of this there is no satisfactory evidence. Soluble peptonate and 
albuminate of iron are put on the market by a number of manufacturers. 

Schmiedeberg found in the liver an iron compound which does not seem 
to resemble the ordinary salts, for it is only blackened by sulphides after 
sometime, and in other ways shows resemblances to the "organic iron," 
such as the hsematogen of the yolk of egg. It would seem to stand midway 
between the ordinary dissociable salts and haemoglobin, for it reacts to 
ammonium sulphide more tardily than the former, while the latter is not 
affected by this reagent. Schmiedeberg named this compound, which is 
an iron-containing proteid, Ferratin. He attempted to form a similar sub- 
stance synthetically from the white of egg, and obtained a body containing 
6-8 per cent, of iron, which reacted similarly with sulphide, and which he 
failed to dissociate by electrolysis. Believing it to be identical with the 
hepatic ferratin, he advised its use in chlorosis as being a natural food iron. 
It is impossible to state from these reactions, however, that the two sub- 
stances — the hepatic and the artificial ferratin — are identical, and, in fact, 
Macallum finds that the former fails to give the hiematoxylon test, while the 
latter yields it readily. 

Artificial ferratin is partially decomposed in the stomach into ordinary 
inorganic salts, but there seems reason to believe that it is absorbed more 
easily than the usual preparations, and it is not irritant to the stomach and 
does not often give rise to dyspepsia. On the whole, ferratin seems a good 
preparation for use in chlorosis, but possesses no such specific virtues as have 
been attributed to it by enthusiastic advocates, and it has the disadvantage 
of being very much more expensive than most other preparations. It is 
given in powder or pill, or in solution as a sodium compound, in quantities 
of 0.5-1.5 G. (8-20 grs.) per day. 

Carniferrin is an iron compound of carniphosphoric 1 (phosphosarkinic) 
acid, which is obtained from beef extract. It contains 35 per cent, of iron, 
and seems to bear the same relation to the inorganic salts and to haemo- 
globin as artificial ferratin, for while it reacts slowly to sulphide, it gives the 
hsematoxylon test. It has been highly recommended in chlorosis, as it does 
not irritate the stomach and is rapidly absorbed. It is given in dose.-- of 
0.5 G. (8 grs.) three times a day in powder, and like ferratin, is soluble in 
alkaline solutions. 

The hsematogen of the yolk of egg, another organic iron of the same type 
as ferratin and carniferrin, is obtained in too small quantity to be available 
for therapeutic use, but seems to be absorbed readily. 

Other proteid compounds which have been advised are formed from yolk 
of egg or from casein, by the addition of iron salts. 

Blood has been used in therapeutics by uncivilized peoples since time 
unknown, and has also been recommended in modern medicine in the 
treatmeut of chlorosis, in which it is administered by the mouth, and also 
hypodermically, though the latter method is difficult to carry out aseptically. 
Hxmoglobin has also been advertised largely of late years in a more or less 
impure form. In the stomach, haemoglobin, whether contained in blood Of 
as crystals, is changed to haematin ; Abderhalden found thai both hemo- 
globin and hseinatin are absorbed and lead to an increase in the hemoglo- 
bin of the blood. Hsemol and hnemogallo! are prepared from blood by agitat- 
ing it with zinc and with pyrogallol respectively, and have been strongly 
recommended by their discoverer, Robert, and by some clinicians, bu1 
been found by others of less value than the old inorganic salts. 

1 Carniphosphoric or phosphosarkinic acid (Ger., Fleischsaure) is a compound of 

phosphoric acid and antipeptonc (C 10 H 15 N 3 O 6 ). 
43 



674 THE HEA VY METALS. 

The " organic" iron preparations therefore seem to have little to recom- 
mend them as superior to the " inorganic," except that ferratin and carni- 
ferrin are probably more rapidly absorbed, and are less liable to cause 
dyspepsia than many of the older salts. Where there is special difficulty in 
administering the more commonly used forms, these two may be substituted 
for them with advantage, but they seem to be unnecessary in ordinary cases. 
In regard to the other preparations mentioned, further and impartial inves- 
tigation is required before their place in therapeutics can be determined. 

Bibliography. 

Meyer u. Williams. Arch. f. exp. Path. u. Pharm., xiii., p. 70. 

Kobert. Ibid., xvi., p. 361. 

Hamburger. Zts. f. phys. Chem., ii., p. 191 ; iv., p. 248. 

Bwnge. Ibid., ix., p. 49 ; xiii., p. 399 ; xvi., p. 173 ; xvii., p. 63. 

Hausermann. Ibid., xxiii., p. 555. 

Bunge, Quincke. Cong. f. inn. Med., 1895, p. 133. 

Marfori. Arch. f. exp. Path. u. Pharm., xxix., p. 212. 

Schmiedeberg. Ibid., xxxiii., p. 101. 

Gottlieb. Ibid., xxvi., p. 139. Zts. f. phys. Chem., xv., p. 371. 

Jakobj. Arch. f. exp. Path. u. Pharm., xxviii., p. 256. 

Socin. Zts. f. phys. Chem., xv., p. 93. 

Molisch. Sitzungber. Wien. Akad., ciii., 1894, Abt. i., p. 554. 

Kunkel. Pfliiger's Arch., 1., p. 1 ; lxi., p. 595. 

Stockman. Brit. Med. Journ., 1893, i., p. 881. Journ. of Phys., xviii., p. 484 ; xxi., 
p. 55 (with Greig). 

Scherpf. Bossbach's Untersuchungen, ii., p. 145. 

Macalum. Journ. of Phys., xvi., p. 268 ; xxii., p. 92. 

Woltering. Ztschr. f. phys. Chem., xxi., p. 186. 

Hall. Arch. f. Anat. u. Phys., 1894, p. 455 ; 1896, p. 49. 

Pohl. Arch. f. exp. Path. u. Pharm., xxv., p. 65. 

Gaule. Deutsch. med. Woch., xxii., pp. 289, 373 (1896). Zts. f. Biol., xxxv.,p. 
377. 

Hochhaus u. Quincke. Arch. f. exp. Path. u. Pharm., xxxvii., p. 159. 

Hamaskin, Kumberg, Busch, Stender, Anselm, Samojloff. Arb. a. d. pharm. Instit. zu 
Dorpat, vii., viii., ix. 

Cloetta. Arch. f. exp. Path. u. Pharm., xxxvii., p. 69; xxxviii., p. 161; xliv., 
p. 363. 

Hofmann. Virchow's Arch., cli., p. 488. 

Filippi. Ziegler's Beitrage zur path. Anat., xvi., p. 462. 

Mbrner. Zts. f. phys. Chem., xviii., p. 13. 

Buzdygan. Wien. klin. Woch., 1897, p. 713. 

Voit. Zts. f. Biol., N. F., xi., p. 387 (1893).^ 

Glaevecke. Arch. f. exp. Path. u. Pharm., xvii., p. 466. 

JVeuss. Zts. f. klin. Med., iii., p. 1. 

Eger. Ibid., xxxii., p. 335. 

V. Noorden. Berl. klin. Woch., 1895, p. 181. 

Hari. Arch. f. Verdauungskrank. , iv., p. 160. 

Abderhalden. Ztschr. f. Biologie, xxxix., pp. 113, 193, 487. 

Muller. Virchow's Arch., clxiv., p. 436. 

IV. LEAD. 

Lead is used to some extent in therapeutics, but its chief interest 
from a medical point of view lies in the frequency with which it gives 
rise to chronic poisoning, and in the diversity of the symptoms pre- 
sented in that condition. 

Solutions of lead salts precipitate albumin, and the precipitate is 
more dense and heavy than that of mercury, and is insoluble in excess 
of the salt. This precipitate is formed when lead solutions are applied 
to the mucous membranes, and protects them from the penetration of 
the metal, so that lead is one of the least corrosive, and one of the most 



LEAD. 675 

astringent of the heavy metals. This absence of corrosion is only in 
part due to the character of the precipitate, for lead forms insoluble 
and therefore non-irritant salts with two of the most corrosive acids 
hydrochloric and sulphuric acids. The soluble nitrate of lead is 
comparatively irritating because it is readily dissociated and also be- 
cause the nitric acid formed by its contact with proteid is itself corro- 
sive. The only soluble salts which are largely used are the acetates, 
and these are slowly dissociated and the acid is only slightly active, so 
that the astringent metallic ion alone comes into play. 

Symptoms. — In ordinary therapeutic doses, the acetate of lead 
(sugar of lead) has a sweetish, metallic taste followed by a feeling of 
astringeucy, and induces no symptoms except constipation. The stools 
after lead are often said to be dark in color from the sulphide formed 
in the intestine, but this does not seem to be the general rule. Prob- 
ably little lead is absorbed from an ordinary dose of the acetate ; at 
any rate no symptoms arise from the general action of the metal ab- 
sorbed. 

Lead acetate solutions applied to the skin have no effect, but mucous 
membranes, or exposed tissues, such as ulcers, are covered with a thin 
pellicle of albuminate, which serves to protect them from irritation, 
and thus promotes their healing. 

When very large quantities of acetate are swallowed, particularly if 
in a concentrated form, they give rise to the ordinary symptoms of irri- 
tant poisoning, nausea, vomiting, pain in the abdomen, violent purg- 
ing or sometimes constipation, blood in the vomited matter and stools, 
great thirst, weakness, and collapse. In some instances in which the 
patients recovered from these symptoms, they subsequently suffered 
from chronic lead poisoning, but apart from these, nothing in the course 
of acute lead poisoning suggests the absorption of the metal, all the 
symptoms being obviously due to the local effects on the stomach and 
bowel, and to the consequent collapse. In fact the effects of a sudden 
absorption of lead in man are unknown. 

In animals also, some difficulty has been met in inducing the symptoms 
due to the action of large quantities of lead in the tissues, because most 
forms of lead injected into the vessels precipitate the proteids of the blood 
and cause embolism, while, on the other hand, only local symptoms can be 
induced by its administration by the mouth. Harnack investigated this 
point by injecting salts of lead-triethyl, in which the metal is not contained 
in a dissociable form, but which is decomposed in the tissues and then gives 
rise to lead symptoms. In this way he hoped to be able to elucidate the 
symptoms of chronic lead poisoning, but his results have not been of much 
value for this purpose, although they are of some interest. In the frog ho 
found that his compound produced general paralysis, which he ascribed to 
action on the muscles, but which Wyss later stated to be due to action on the 
central nervous system. Harnack describes the muscles as being easily 
fatigued, and gives some further peculiarities induced by lead in them, hut 
Wyss found in apparently equally satisfactory experiments that the muscles 
were practically unaffected at death. In the dog large doses of lead injected 
into a vein induced weakness and paralysis, violent diarrhoea, chorea-like 
movements, tremors, which often assume the appearance of true convulsions, 



676 THE HEAVY METALS. 

and ataxia. The diarrhoea was attended by severe colic, and both of these 
symptoms were removed by atropine. It would therefore appear that the 
colic is here due to nervous influences, and not to the muscle of the intestine 
being immediately acted upon, for atropine paralyzes only the terminations 
of nerves. The diarrhoea Harnack found to be due to violent contrac- 
tions of the intestinal walls, which maintained a certain degree of contraction 
even when no peristaltic wave was passing. This action of lead upon the 
intestine is of interest, because it bears a close relation to the colic observed 
in chronic lead poisoning in man, although here there is generally con- 
stipation, and also because it connects lead with the other heavy metals, 
all of which have more or less specific action on the intestine. The ataxia 
and other brain symptoms also have their counterpart in the brain symptoms 
of chronic poisoning in man. 

A single dose of a lead salt does not generally give rise to any symp- 
toms which would indicate the absorption of the metal, but the con- 
tinued ingestion of small quantities by way of the stomach, or by 
inhalation by the lungs, induces chronic poisoning, which can be ex- 
plained only by its absorption. There seems some reason to believe 
that lead is absorbed from the unbroken skin, though it is possible that 
some of the metal was carried to the mouth and swallowed with the 
food in the cases on which the statement is founded. Lead is appar- 
ently Absorbed more rapidly than most of the metals except mercury, 
and remains lodged in the tissues a long time, the excretion taking 
place only very slowly. It is found in most organs in cases of poison- 
ing, particularly in the liver and kidney. It is Excreted in the urine, 
the bile, the secretion of the intestinal epithelium, and in milk and 
saliva. It is still disputed whether it is eliminated by the skin glands, 
or whether the lead often seen on the skin in cases of poisoning is not 
simply deposited there as dust from the air. 

Chronic Lead Poisoning is the commonest of all forms of metallic 
poisoning, and at the same time one of the most insidious. It is al- 
ways accidental, and although it is most common in workers in lead, 
may occur in persons who are not apparently liable to come in contact 
with the metal. There is no question that some people are much more 
susceptible to lead than others. Anaemia and weakness from any cause 
are generally believed to predispose to the disease, women and children 
are more liable to it than men, and alcoholism and previous lead in- 
toxication increase the tendency to the attack. Relapses are very 
common, and may occur years after the first symptoms, even although 
there has been no further exposure in the interval. Lead smelters, 
workers in white lead factories, painters, plumbers and typesetters are 
very liable to lead poisoning from their continually handling the 
metal ; but other trades are not exempt from it, and sometimes the 
channels by which it gains entrance to the body are very obscure. 
Some of the more common causes of poisoning are lead water-pipes or 
cooking utensils, lead used to close tins of meat or fruit, and lead in 
hair dyes. Formerly a common source of poisoning was wine and 
cider to which lead had been added to reduce the acidity. A consider- 
able number of cases of poisoning have been recorded from the use of 
lead preparations as abortifacients. "' 



LEAD. 677 

The symptoms of chronic lead poisoning vary greatly in different 
cases, sometimes only one or two organs being attacked, in others the 
whole economy appearing involved in the disorder. The symptoms 
may be divided into groups for convenience, but it is to be noted that 
many of these appear to be closely inter-connected, and that in many 
cases it is impossible to decide whether a set of symptoms is due to 
direct action upon a single organ, or to the simultaneous disease of 
several. 

The Mouth, Stomach and Digestion very often give early indications 
of lead poisoning. The patient complains of loss of appetite, nausea; 
constipation, wasting, a metallic taste and foetid breath, and a blue- 
black line is seen along the margin of the teeth where they enter the 
gums. This " lead line " is due to the precipitation of lead sulphide 
by the hydrogen sulphide produced by the action of bacteria, and it is 
often absent, especially where the teeth are not carious and are kept 
clean. The metallic taste seems due to the excretion of lead in the 
saliva, and the loss of appetite may arise from the same cause. These 
symptoms may be produced in animals also. Virchow and Maier 
found in one case in man the gastric epithelium in a state of fatty de- 
generation, and proliferation of the connective tissue of the mucous 
membrane. 

Another early symptom is Anaemia, which may be due in part to the 
malnutrition, but is attributed mainly to an abnormal destruction of 
the red cells of the blood ; the white corpuscles are increased in many 
cases but not in all. It is often accompanied by jaundice, with the 
highly pigmented urine and other symptoms which usually follow the 
liberation of large quantities of haemoglobin from the breaking up of 
red cells. It is stated that the red blood-cells often contain granules 
staining with basophile dyes and indicating incomplete disappearance 
of the nucleus; this change may present itself before any other symp- 
tom. The anaemia is often very marked, and is sometimes the chief or 
only symptom of lead poisoning ; according to some authorities, it ie 
present in a greater or less degree in the majority of white-lead work- 
ers, and it leads to weakness, languor, and in young women often to 
amenorrhoea. Abortion is very often met with in lead poisoning, and 
in women employed in lead works who do not show any marked symp- 
toms of disease. The children of parents suffering from lead are often 
weak and undersized, and a very large proportion of them die in early 
infancy. 

One of the commonest symptoms is Lead Colic, painters' colic, colics 
saturnina or colica Pictonum. This generally sets in suddenly, and is 
accompanied in most cases by obstinate constipation, in a very small 
proportion by diarrhoea. Paroxysms of the most acute agony are fol- 
lowed by intervals of comparative freedom from pain, but in these in- 
tervals some tenderness of the abdomen may be complained of, while 
during the attack pressure generally relieves the pain, 'flic colic I 
for several days, or a week, and then disappears, but is liable to return 
at intervals. The abdomen is generally hollow, retracted and bard, 



078 THE HEAVY MET ALU. 

and during the acute spasms the patient often gains some relief by lying 
on his face with the fists pressed against the umbilical region, to which 
the pain is usually referred. Vomiting is frequently present, the pulse 
is slow and very hard, especially during the acute crises, while the 
respiration may be accelerated. The urine is scanty, and, according 
to Stokvis and Nakorai, contains hsematoporphyrin. 

The cause of lead colic is evidently spasm of the intestine, which is 
generally attributed to action on the nervous ganglia of the walls. It 
can be induced in animals, and according to Harnack, is relieved by 
atropine, which would support the belief that it is of nervous origin. 
The blood-pressure is raised in man, not only during the spasms, but 
also in the intervals. This contraction of the vessels and the slowing 
of the pulse is often said to be reflex from the pain, but this seems to 
be disproved by the fact that it remains during the intervals. Some 
writers have therefore regarded the colic and its attendant symptoms 
as due to a vascular spasm, and have supported this by showing that 
nitrite of amyl, which dilates the vessels, also relieves the colic. 1 

On the whole, the colic appears to be of nervous origin, but whether 
the focus of disease lies in the wall of the intestine, in the nerves 
leading to it, or in the central nervous system, it is impossible to de- 
termine at present. 

Another common result of chronic lead poisoning is Paralysis, lead 
or painters 7 palsy, paralysis saturnina, which is almost invariably 
limited to certain groups of muscles, the extensors of the forearm. 
It is bilateral in the great majority of cases, but sometimes involves 
only one arm. The affection generally begins in the middle and ring 
fingers, which cannot be extended, then spreads to the index and little 
finger, and afterwards to the thumb and wrist. The fingers remain 
flexed and later the wrist is similarly affected, so that the condition is 
often known as wrist-drop. Even after all the other muscles of the ex- 
tensor surface of the forearm are involved, the supinator longus remains 
normal as a general rule. The muscles affected atrophy rapidly, and 
in old cases contracture of the flexor muscles sets in, when the limb 
becomes immovable and has a characteristic claw-like appearance. 
More rarely other regions are affected, such as the laryngeal muscles (in 
the horse), the external rectus of the eye, or the muscles of the leg. In 
rabbits and guinea-pigs several observers have succeeded in inducing 
paralysis of the hind limbs, and the legs are said to be affected very 
often in young children. When paralysis is complete, the induced 
electric current fails to cause contraction, whether it is applied to the 
muscle or to the nerve, but the galvanic shock induces an abnormally 
strong contraction when it is passed through the muscle, the make 
shock having more effect than the break ; the contraction is more pro- 
longed, the relaxation slower than in normal muscles. This reaction 

1 Maier attributed the colic to a sclerosis of the intestinal ganglia, which he found 
to occur in animals treated with lead acetate ; but this explanation is opposed to the 
fact that complete recovery generally follows, and his experiments are open to the 
objection that the sclerosis may be due to the local action of the lead on the bowel, as 
he administered the acetate by the mouth for prolonged periods. 



LEAD. 079 

of degeneration is said to occur in the other muscles in lead poisoning, 
even when no paralysis can be detected in them. The cause of lead 
palsy is still undecided, for while in some cases there is undoubtedly a 
peripheral neuritis and nerve degeneration, and no anatomical lesion 
of the spinal cord, yet in others very distinct degeneration of the cord, 
particularly of the cells of the anterior horn, has been observed. Al- 
though the majority of pathologists at the present time are of the 
opinion that the lesion is a peripheral neuritis, and that the degenera- 
tion of the cord is either a consequence of this, or is perhaps an en- 
tirely independent lesion, some authorities hold that the focus of dis- 
ease is situated in the cord, and that the neuritis is merely an extension 
of the process. They explain the absence of visible changes of the 
cord in some cases by supposing that the function of the cell is de- 
stroyed by the poison, without actual anatomical lesion. A third view 
which was held formerly, but has been abandoned except by a very 
few, is that the original lesion is in the muscles. Peripheral neuritis 
has been elicited repeatedly in animals. 

Local Anaesthesia is also observed occasionally, though much more 
rarely than paralysis. It is generally sudden in its onset, but may be 
preceded by numbness or tickling of the skin, and generally lasts only 
one or two weeks, when sensation returns again to the part. 

Lead Arthralgia is more commonly observed, perhaps because it is 
so much more evident. It consists in sharp lancinating or boring 
pains in the joints, bones, or the flexor muscles around the joints, the 
intensity of the pain being comparable only to that of lead colic. It 
sets in suddenly, usually in the night, and generally disappears as sud- 
denly. This symptom is not in any way dependent on the gout which 
is often induced by lead poisoning, and its explanation, like that of 
the anaesthesia, is quite unknown. 

Lead Amblyopia, or blindness, is one of the rarer affections. The 
sight may be lost completely, or may only be dim, and the onset may 
be sudden or gradual. In some cases the ophthalmoscope gives no 
clue to the cause of the blindness, in others an acute papillitis is made 
out. Stood ascribes the amblyopia to several causes, which may each 
give rise to it separately or may act together. The first of these is 
a neuritis of the optic nerve in the eye, which gives distinct ophthal- 
moscopic appearances. In the second the neuritis may be descend-* 
ing or retrobulbar, and may induce little visible change, while the 
third cause of blindness may be uraemia with an effusion into the optic 
sheath, and a fourth is albuminuric retinitis, these two last forms 
being due not to a direct action on the nerve, but to the nephritis in- 
duced by the poison. The sudden cases of blindness are probably due 
to uraemia, and the prognosis in all forms depends on the duration o\' 
the neuritis, and, in the case of albuminuria, on tin 1 extent to which the 
kidney is involved. In early cases of neuritis, the disease can gener- 
ally be arrested and even complete restitution may take place, but if it 
be neglected, optic atrophy follows. 

Under saturnine Encephalopathia, a number of disorders of tin- brain 



b'80 THE HEAVY METALS. 

are classed together. They are comparatively rare at the present time, 
and their onset generally indicates long standing and neglected lead 
intoxication, although in some cases the patient has been shown to be 
exposed to the poison for only a short period. An attempt has been 
made to divide the symptoms of encephalopathia saturnina into four 
groups, but as the author himself remarks, one of the most character- 
istic features is the rapidity with which the disease changes from one 
type to another, and the diversity of the symptoms present at one 
time. These cerebral symptoms sometimes appear suddenly, while in 
other cases they are heralded by violent headache, giddiness and sleep- 
lessness, or by amblyopia, deafness, great depression, stupor, weakness, 
and tumor. Later, sudden mania and delirium, with convulsions re- 
sembling chorea or epilepsy, hallucinations and illusions indistinguish- 
able from those of alcoholic delirium, sudden apoplectic paralysis, 
ataxia, partial analgesia, hyperesthesia, or coma may occur separately 
or in succession. Oliver states that the encephalopathy symptoms are 
especially liable to occur in persons addicted to alcohol. 

In animals cerebral symptoms are readily induced by lead, either 
by intravenous injection (Harnack), or by chronic poisoning with the 
ordinary salts. Chorea, tremors and general convulsions have been 
caused in this way in dogs. 

The encephalopathia is obviously of cerebral origin for the most 
part, although the lower divisions of the central nervous system are 
also involved in many cases. In several autopsies of patients dying 
from lead poisoning, atrophy of parts of the cerebrum, or haemorrhages 
have been found, and very frequently disease of the brain vessels — 
periarteritis, endoarteritis, atheroma or hyaline degeneration — has 
been met with. In other cases of undoubted encephalopathia in man, 
no such lesions have been observed, and in animals poisoned by Har- 
nack's method they are certainly not present. Many of the symptoms 
are obviously not due to these gross lesions, for the suddenness of their 
onset and of the recovery precludes any such explanation, and show 
that lead has also a direct action on the brain cells. Lugaro and 
Schaffer have described some alterations in the chromatin and the 
dendrites of the nerve cells, which they suppose indicate this direct 
aifection ; McCarthy found marked changes in the capillaries of the 
cerebral cortex in a dog which was subjected to the action of lead for 
two months and which presented symptoms of cerebral disorder similar 
to those met with in chronic poisoning in man. 

It must be noted that in addition to these generally recognized symp- 
toms of encephalopathia saturnina, several obscure chronic nervous 
diseases have been ascribed by Putnam and others to lead intoxication, 
and it is certainly possible that its action may prove to be even more 
wide-reaching and insidious than is generally recognized at present, but 
it does not seem profitable to enter upon further details in the present 
state. of the subject. 

Another organ acted on by lead, especially in prolonged poisoning, 
is the Kidney, which is often found to present a typical red granular 



LEAD. 681 

nephritis. During life the urine presents the ordinary appearances of 
this disease, being copious in amount and of low specific gravity, and 
containing comparatively small quantities of albumin or casts. In 
some cases in man, the kidney has presented a mixture of parenchyma- 
tous and interstitial disease, while in animals the parenchyma alone is 
affected, perhaps because the experiments have not lasted long enough. 
The disease of the kidney from lead poisoning, as from other sources, 
may cause dropsy, uraemia and amblyopia, but it is to be noted that 
the brain and eye may be affected in cases in which there is no 
nephritis. 

Gout is very common in lead poisoning, which evidently predisposes 
to this disease, if it does not actually cause it, for Garrod states that in 
one-fourth of the cases of gout treated by him there was a history of 
lead poisoning. It occurs only after prolonged exposure to the metal, 
and differs from ordinary gout in the rapidity with which it spreads 
from one joint to another, as well as in some other features (Luethje). 
Thus gout is seen without nephritis and vice versa, the two affections 
being quite independent of each other. The uric acid of the urine is 
not increased, while that of the blood is said to be abnormally high. 
In districts where ordinary gout is rare, lead poisoning seldom leads 
to it, but where ordinary gout is met with, it is a fairly common com- 
plication of saturninism. 

Lead poisoning runs no definite course. As a general rule the 
anaemia, wasting, constipation and weakness appear early, and then 
colic may follow, or paralysis, or arthralgia. Nephritis, encephalopa- 
thia, anaesthesia and gout are rarer, and as a rule only occur in very 
prolonged poisoning. Any one of these symptoms may be present 
alone, and the diagnosis is then very difficult. In doubtful cases the 
urine ought to be examined after the administration of iodide, or the 
stools may be tested for lead. Every case in which lead is found in 
the urine is not necessarily one of lead intoxication, however, for it 
has been detected in a number of perfectly healthy individuals. 

It is impossible at present to give any general explanation for the 
diversity of the forms of chronic lead poisoning. The central nervous 
system is certainly acted on, both in its higher and lower divisions, 
but it is still disputed how far the paralysis, arthralgia and anaesthesia 
are symptoms of central action, and how far they are due to peripheral 
neuritis. All of the symptoms, however, except those from the mouth, 
stomach and kidney, and the anaemia and gout seem to be due to affec- 
tions of either the central or peripheral nervous system. The lead 
line, metallic taste and nausea, and perhaps the constipation, would 
seem to be connected with the excretion of the metal along the ali- 
mentary canal, while the renal action is probably of the same nature 
as that inducing periarteritis in the brain and, as is alleged, in the 
lungs under some conditions. The anaemia indicates an action on the 
red cells of the blood, and the gout some disturbance of the general 
nutrition. Attempts have been made to elucidate the nature of t In- 
action on metabolism by estimating the urea and other constituents of 



682 TILE UEA VI METALS. 

the urine, but no important light has been thrown on it by this means, 
nor in fact are significant results to be hoped for in a disease which 
offers so many and so diverse types as lead poisoning. 

Lead acts upon so many tissues that it might be expected to have 
some distinctive action upon the simpler organisms, but, as a matter of 
fact, it seems less poisonous to them than most other heavy metals. 

Preparations. 

Plumbi Acetas (U. S. P., B. P.), lead acetate, sugar of lead (Pb(C 2 H. t 2 ) 2 
-f 3H 2 0), forms colorless crystals, with a sweetish, astringent, afterwards 
metallic taste, very soluble in water, less so in alcohol. 0.05-0.3 G. (1-5 
grs.). 

Unguentum Plumbi Acetatis (B. P.), 4 per cent. 

Suppositoria Plumbi Composita (B. P.) ; each contains 3 grs. of lead acetate 
and 1 gr. of opium. 

Pilula Plumbi cum Opio (B. P.) contains about 12J per cent, of opium. 
2-4 grs. 

Liquor Plumbi Subacetatis (U. S. P.), Liquor Plumbi Subacetatis Fortis (B. P.), 
Goulard's extract, an aqueous solution containing about 25 per cent, of lead 
subacetate (approximately Pb(C 2 H 3 2 ) 2 PbO). When exposed to the air, the 
insoluble lead carbonate is formed. The subacetate solutions are alkaline in 
reaction. 

Liquor Plumbi Subacetatis Dilutus (U. S. P., B. P.), lead water, Goulard's 
lotion or water, a solution containing about 7.5 parts (3 parts B. P.) of the 
subacetate in 1,000 parts of water. 

Glycerinum Plumbi Subacetatis (B. P.). 

Unguentum Glycerini Plumbi Svbacetatis (B. P.). 

Ceratum Plumbi Acetatis (U. S. P.), Goulard's cerate. 

Plumbi Carbonas (U. S. P., B. P.), white lead ((PbC0 3 ) 2 Pb(OH) 2 ). 

Unguentum Plumbi Carbonatis (U. S. P., B. P.). 

Plumbi Iodidum (TJ. S. P., B. P.) (Pbl 2 ). 

Emplastrum Plumbi Iodidi (B. P.). 

Unguentum Plumbi Iodidi (U. S. P., B. P.). 

Plumbi Oxidum (U. S. P., B. P.), litharge (PbO). 

Plumbi Nitras (IT. S. P.) (Pb(N0 3 ) 2 ). 

Lead plaster or diachylon plaster, Emplastrum Plumbi, is formed from the 
oxide but is mentioned elsewhere. (See Part VI.) 

Therapeutic Uses. — Lead is used in therapeutics only for its astrin- 
gent action. The acetate is prescribed internally in diarrhoea, gener- 
ally along with opium, and always in pill form, as the solution would 
act on the stomach and have less effect on the bowel. It has been 
tried in dysentery and cholera, but has proved of little value. Lead 
has also been advised in cases of haemorrhage from the lungs, kidneys 
and uterus, but has no astringent effect in these conditions, because it 
is slowly absorbed, and, besides, what reaches the blood does not act 
on the vessels. If lead preparations are of any value in these affections, 
and this is denied by many authorities, it can be explained only by 
some reflex action from the stomach and bowel. Still less reason is 
there for its use in nephritis, cystitis, and similar conditions. 

Externally, a solution of the acetate, or the dilute solution of the 
subacetate is used as an astringent lotion in burns, and as an injection 
in gonorrhoea. White lead has been advised as a dusting powder in 



LEAD. 683 

burns and skin affections, but is not superior in any way to other 
similar preparations, and is liable to be absorbed. Nitrate of lead has 
a reputation in the treatment of onychia. 

Lead ought not to be employed externally or internally except for 
a short time as otherwise symptoms of poisoning may arise. 

Poisoning. — In acute lead poisoning, the indications are its removal 
from the stomach by washing, and its precipitation, which may be 
best accomplished by solutions of the sulphates such as of magnesium 
sulphate. In the absence of the sulphates, white of egg or milk is 
given to form the insoluble albuminate. 

In chronic poisoning, the general treatment is the removal of the 
patient from the danger of further poisoning, the administration of 
iodide of potassium, and nutritious, strengthening diet. The iodide of 
potassium has been said to accelerate the elimination of lead by the 
kidneys, but according to Lehmann's experiments is not superior to 
the bromide or the chloride of potassium, and it has been recently denied 
that it has any effect on the excretion by the urine or by the intestine, 
by which most of the lead escapes from the body. In practice, how- 
ever, the iodide is always used. Diuretics may be prescribed, and 
hot baths ; sulphur baths are especially recommended, and massage is 
said to hasten the elimination of the poison. 

In colic, morphine or opium is often necessary to allay the pain. 
Belladonna or atropine is used less frequently, and nitrite of amyl is 
said to be efficient for a short time. In the intervals between the 
paroxysms, a saline cathartic is often necessary to relieve the constipa- 
tion, or if the vomiting prevents this, a large enema may be thrown 
into the bowel. 

In arthralgia, the pain may necessitate the giving of opiates. In 
anaesthesia and encephalopathia, the treatment is expectant and symp- 
tomatic ; for instance, in mania, or violent delirium, chloral may be 
necessary. 

In paralysis, strychnine may be used along with the general treat- 
ment, but the chief reliance is to be placed on the electrical stimula- 
tion of the paralyzed muscles, first with the galvanic current, and, as 
recovery sets in, with the induction coil. Massage of the muscles is 
also of benefit. 

Nephritis and gout due to lead poisoning are to be treated in the 
same way as those arising from other causes. 

In lead works and paint factories, much may be done to prevent lead 
poisoning. Dust is to be avoided as much as possible, and where this 
is necessarily present, the rooms ought to be thoroughly ventilated. 
The necessity of frequent bathing and of thorough washing before 
meals ought to be impressed on the workmen, and no food i- t<> be 
admitted to the works. A lemonade made with sulphuric acid is often 
recommended as a prophylactic measure with the object o\' changing 
the lead to the insoluble sulphate and thus rendering it less readily 
absorbed. Poisoning may, however, be induced by lead sulphate. 
though less often than by the carbonate, which is dissolved by water 



C84 THE HEAVY METALS. 

in the presence of free carbonic acid, and which is changed to the 
slightly soluble chloride in the stomach. 

When symptoms of poisoning have appeared, the patient ought not 
to be allowed to work again, or at least only after a long interval. 
Weak and anaemic men ought not to be admitted as workmen, and 
women are not to be employed in lead works more than can be 
avoided. 

Bibliography. 

Harnack. Arch. f. exp. Path. u. Pharm., ix., p. 152. 
Wyss. Virchow's Arch., xcii., p. 193. 
Maier. Ibid., xc., p. 455. 

Annuschat. Arch. f. exp. Path. u. Pharm., vii., p. 45 ; x., p. 261. 
Lehmann. Zts. f. physiolog. Chem., vi., p. 528. 
Harnack. Deutch. med. Woch., 1897, p. 8. 
Mann. Brit. Med. Jour., 1893, i., p. 401. 
Miura, Berl. klin. Woch., 1890, p. 1005. 
Oddo et Silbert. Rev. de Med., 1892, p. 295. 
Gaucher. Ibid., 1881, p. 877. 

Riegel. Deutsch. Arch. f. klin. Med., xxi., p. 175. 
Borgen. Ibid., lvi., p. 248. 

Etlenberger u. Hqfmeister. Arch. f. Thierheilkunde, x., p. 216. 
Westphal. Archiv f. Psychiatrie, xix., p. 620. 
Stieglitz. Ibid., xxi v., p. 1. 
Cera. Ibid., xxix., p. 566. 

Luethje. Ztschr. f. klin. Med., xxix., p. 266; xxxi., p. 112. 
Stood. Arch. f. Ophthalmol., xxx., iii., p. 215. 
Schroeder. Ibid., xxxi., i., p. 229. 
Cornil et Brault. Journ. de l'Anat., 1883, p. 205. 
Coene U Ajutolo. Ziegler's Beitriige, iii., p. 451. 
Charcot. Arch, de Physiol., 1881, p. 126. 
Walton. Boston Med. and Surg. Jour., ex x iii., p. 411. 
Webber. Ibid., exxv., p. 462. 

Putnam. Ibid., cxvii., pp. 73, 596; exxviii., p. 187. 
Ebstein. Virchow's Arch., exxxiv., p. 541. 
Eichhorst. Ibid., cxx., p. 217. 
Lugaro. Centralbl. f. Physiol., 1897, p. 211. 
Schaffer. Ung. Archiv f. Med., ii., p. 43. 
Provost et Binet. Rev. Med. de la Suisse Romande, 1889. 
Lorimer. Brit. Med. Jour., 1886, ii., p. 163. 

Oliver. Lancet, 1891, ii., p. 530. Lead poisoning, London, 1891. 
Virchow. Berl. klin. Woch., 1884, p. 75. 
Trimborn. Centralbl. f. klin. Med., 1891, p. 44. 

White and Pepper. Trans, of Amer. Assoc, of Physicians, 1901, p. 410. 
McCarthy. Univ. of Pennsylvania Med. Bull., January, 1902. 



V. COPPER. 

Copper seldom gives rise to poisoning, and is much less frequently 
used in medicine than many of the other heavy metals. The soluble 
salts precipitate proteids from solution, and are therefore astringent 
when applied to the mucous membranes and to wounded surfaces. In 
larger quantities they are somewhat irritant and corrosive, although 
much less so than mercury. 

Symptoms. — The copper salts have a harsh, metallic, astringent 
taste, and when swallowed in some quantity cause nausea, salivation 
and vomiting. The most of the salt is thus removed, and no further 
symptoms are observed. Large quantities, however, induce corrosion 



COPPER. 685 

of the walls of the stomach and intestine, and give rise to violent vom- 
iting and purging, the copper giving a blue or green color to the vom- 
ited matter and the stools, and blood appearing in them later from the 
corrosion of the mucous membrane. Violent pain in the abdomen is 
complained of, and the usual symptoms of acute corrosive poisoning 
may follow — collapse, with weak pulse and respiration, headache, 
giddiness, unconsciousness, delirium, coma, convulsions and paralysis. 
These may prove fatal in a few hours, but more frequently the patient 
lives for several days to eventually sink from exhaustion. 

The nausea, vomiting and purging of acute copper poisoning are due to the 
local effect on the mucous membranes of the stomach and intestine. In feet, 
although some copper is absorbed in these cases, there is no reason to sup- 
pose that any of the acute symptoms are due to it, for they are all induced 
by other poisons which act only as gastro-intestinal irritants. 

It is still disputed whether chronic copper poisoning occurs in man. The 
question is of great hygienic interest, because copper is used very often to 
give color to preserved vegetables, such as peas, is added to flour to improve 
the bread, and may enter into the food from the use of copper cooking ves- 
sels, and in a variety of other ways. In copper and brass workers, gastro- 
intestinal catarrh, or colic and diarrhoea, occur occasionally and are ascribed 
to the copper swallowed in the course of their occupation. The dust inhaled 
may similarly cause laryngeal irritation and bronchitis. The skin and hair 
have often a greenish tint, and a green line on the teeth, just where they 
enter the gums, is known as the copper line ; but it is believed that these are 
due largely to the copper dust deposited on the skin, hair and teeth, and not 
to the excretion of the metal. Local paralysis, anaemia, tremor, emaciation 
and cutaneous eruptions are said to have followed these symptoms in some 
cases, and have been held to indicate that copper is poisonous after absorp- 
tion, but it may fairly be doubted whether these symptoms are really due to 
the copper or to the lead, arsenic and other poisons often associated with it. 
It is certain that only a very small proportion of workers suffer from any 
symptoms whatever, and that the great majority enjoy excellent health. 
Furthermore, copper has been taken in the form of the metal, or of its soluble 
salts for prolonged periods without any symptoms being elicited except those 
of slight intestinal catarrh and some nausea. Animals have been fed with 
food containing large doses of copper for many months, apparently without 
any symptoms of poisoning, and copper is found so regularly in the tissues 
of man and animals that it may be regarded as a normal constituent, although 
its function is altogether unknown and it may be merely stored up on its way 
to excretion. Of course it is possible that there exists in certain persons an 
idiosyncrasy for copper, and that these suffer from the ingestion of quantities 
which are harmless in others. But until the symptoms have been mere def- 
initely determined, and have been shown not to arise from the other poisons 
associated with copper, it is impossible to consider this form of intoxication 
as satisfactorily established, and there is no reason to suppose that poisoning 
can be induced by small quantities of copper such as are contained in pre- 
served vegetables or in food cooked in copper vessels. 

In animals the general action maybe elicited by the injection ol' copper 
into the blood or subcutaneously. The ordinary salts are inadmissible by 
the former method, as they precipitate the proteids of the blood and cause 
embolism, and double salts, such as the tartrate of copper and sodium, or 
proteid compounds, such as the albuminate dissolved by means of alkalies, 
have therefore been used. A special form of proteid combination has b< 
formed in the same way as artificial ferratin, and is found to act more slew ly 
than ordinary salts. In the frog, copper induces great weakness and event- 
ually complete paralysis of the spontaneous movements and ol' the heart. 



686 THE HEAVY METALS. 

llarnack attributed this to direct action on the muscle, but later observers 
have found that the central nervous system is primarily affected, and that the 
muscles retain their irritability alter complete paralysis of the spinal cord. 
There is, however, a direct action on the muscles also, for they lose their 
irritability very soon after death, and even before the spontaneous move- 
ments have ceased, the contraction of the muscles on direct stimulation being 
much weaker than usual. Very often fibrillary contractions are observed 
early in the frog, but it is unknown whether these are of central or of peri- 
pheral origin. The heart is somewhat accelerated at first by very small 
quantities, but later becomes slow and weak, and finally ceases in diastole 
before the skeletal muscles are paralyzed ; the changes in the heart are due 
to direct action on the muscle. 

In mammals the intravenous injection of copper does not cause vomiting, 
according to most authors, thus proving that the emetic action is due to the 
irritation of the stomach, and not to any action on the medulla. "When 
large quantities are injected, the locomotion soon becomes slow, clumsy and 
weak, and later, complete paralysis of the spontaneous movements follows. 
The heart and respiration seem equally involved, but the respiration ceases 
somewhat earlier than the heart. The blood-pre&sure rises slightly after the 
intravenous injection of copper, but afterwards falls, partly on account of 
the weakness of the heart, and partly from failure of the vaso motor nerves 
to maintain the contraction of the blood vessels. When an animal survives 
longer, violent, sometimes bloody, diarrhoea is generally induced by copper, 
as by mo4 of tbe other heavy metals. The animals lose flesh rapidly, and 
refuse food, and the urine often contains albumin, and according to some 
authors, haemoglobin and blood. In the rabbit some icterus and anaemia is 
said to occur from the destruction of the red blood cells, and fatty degen- 
eration of the liver, kidney, and heart have been observed. Others have 
found ecchymoses and congestion along the intestine and in the kidney to 
be the chief lesions. Similar results are obtained in rabbits when copper is 
given by the mouth, as this animal is incapable of rejecting the poison by 
vomiting. In the dog, on the other hand, poisonous doses seem to be re- 
moved by vomiting when they are given by the mouth ; it is possible, how- 
ever, that animals may show symptoms of poisoning from the prolonged ad- 
ministration by the mouth of quantities just too small to cause vomiting, and 
in fact a form of chronic poisoning in animals is described by Baum and 
Seeliger. 

Copper is certainly absorbed from the stomach and intestine, for 
large quantities have been found in animals fed on it for some time. 
Baum and Seeliger state that a very large proportion of the poison is 
absorbed when small doses are given, but the proportion lessens as the 
dose is increased. It also passes into the blood from other mucous 
surfaces and from wounds. It is said to have a strong affinity for 
haemoglobin, and to form with it a compound which Kobert has named 
cuprohsemol, and which is stated to be formed very rapidly when 
copper is injected into the blood, the metal leaving the serum and 
attaching itself to the corpuscles at once. The copper absorbed from 
the intestine and stomach is lodged chiefly in the liver, less in the 
spleen, kidney and thyroid. It is excreted in the bile, urine and sa- 
liva, in the intestinal secretions, and in traces in the milk, and is said 
to pass from the mother to the foetus in utero. Copper is found in 
small quantities in these organs and secretions in man and in animals 
that have not been treated with it, but in much larger amount after 
prolonged administration. Taken by the mouth, it fails to cause gen- 



COPPER. 687 

eral poisoning, because it is slowly absorbed, and also because what is 
absorbed is withdrawn from the blood by the liver. 

Copper is found as a normal constituent of the blood in many of the in- 
vertebrates, in which it performs the same function as the iron of the hemo- 
globin in the vertebrates. It has been detected in one of the pigments of 
birds' feathers, and, as has been stated, is so frequently found in the tissues 
of mammals, both wild and domesticated, that it may be regarded as a nor- 
mal constituent. Oysters and other animals take it up in large quantities 
when they live in water rich in copper, and apparently are not injured by it. 
Many of the higher plants, notably the grape vine, are said to be remark- 
ably improved by the sprinkling of copper on their leaves, and this is not 
only from the destruction of parasites, for vines free from any disease show 
a more luxuriant foliage, and bear more and larger fruit than other healthy 
plants, which are not treated with it. On the other hand, copper is a deadly 
poison to several of the lower plants. Thus traces of copper added to tin- 
water in which they live, destroy some of the simpler algae, and Naegeli 
asserts that one part of copper in one thousand million parts of water is 
sufficient to kill these plants. The parasites of the grape vine, potato, apple, 
and other plants are destroyed by spraying the plants with copper, and 
yeast ceases growing in a 0.02 per cent, solution, while penici ilium seems to 
be almost immune to its action. Locke found that the traces of copper 
contained in water distilled in copper vessels was sufficient to destroy 
tubifex (one of the annelid worms) and tadpoles, while Bucholtz states that 
the development of bacteria is stopped by a solution of copper sulphate 
under one per cent, in strength. Copper thus seems to have a very power- 
ful poisonous action on certain living forms and to be harmless to others, 
and the subject deserves further investigation. It is possible that it may 
prove to act prejudicially to some human parasites, and it is certainly less 
dangerous to man than many other remedies used as parasiticides and disin- 
fectants. 

Preparations. 

Cupri Sulphas (TJ. S. P., B. P.) (CuS0 4 + 5H 2 0), large, transparent, deep 
blue crystals, without odor, but with a nauseous, metallic taste, soluble in 
water, scarcely so in alcohol. Dose, as an astringent, 0.015-0.1 G. (]-2 grs.); 
as an emetic, 0.3-0.6 G. (5-10 grs.). 

Therapeutic Uses. — Copper sulphate is used internally only as an 
emetic, and for this purpose ought to be given in about one per cent, 
solution. It acts promptly, and does not leave so much depression 
and nausea as other metallic emetics, and for this reason is unsuitable 
as an expectorant. In phosphorus poisoning it is especially valua- 
ble, as in addition to causing evacuation of the stomach, the metal is 
deposited on the particles of phosphorus and prevents their absorption. 

Externally copper sulphate is used as an astringent injection in 
gonorrhoea, and occasionally as a lotion in ulcers and wound- ; for this 
purpose it is employed in one per cent, solution. The solid crystals 
are sometimes used to touch exuberant granulations lor their astrin- 
gent and corrosive effect. 

The chloride of copper is a much more irritant and antiseptic substance 
than the sulphate. The albuminate of copper, cupratin, which is formed 
from the albuminate by heating with alkalies, and cuprohsemol, a combina- 
tion of copper and haemoglobin, have been suggested recently as non-irritant 
preparations suitable for internal use, but no condition is known at present 
in which the general action of copper is of benefit 



688 THE HEAVY METALS. 

In cases of Poisoning with copper salts, the stomach generally rejects i bi- 
metal by vomiting, and no emetic is required. Non-corrosive compound* 
may be formed by giving milk, egg, or other forms of albumin, tannic acid, 
magnesia, or ferrocyanide of potassium. Morphine may be required for the 
pain, ice to stop the vomiting. 

Bibliography. 

Harnack. Arch. f. exp. Path. u. Pharm., iii., p. 44; xvii., p. 145. 

Curd. Virchow-Hirsch Jahresber., 1887, i., p. 387. 

Klemptner. Ibid., 1895, L, p. 346. 

Lehmann. Arch. f. Hygiene, xxiv., p. 1 ; xxvii., p. 1 ; xxxi., p. 279. 

Filekne. Deutsch. med. Woch., 1895, p. 297; 1896, p. 145. 

Tschirch. Das Kupfer, vom Standpunkte der gericht. Chemie, Toxikologie u. Hy- 
giene, Stuttgart, 1893. 

Schivartz. Arch. f. exp. Path. u. Pharm., xxxv., p. 437. 

Robert. Deutsch. med. Woch., 1805, p. 5. 

De Moor. Arch, de Pharniacodvnamique, i., p. 81. 

Baumu. Seeliger. Centralbl. f. "Physiol., 1896, pp. 714, 752; 1897, p. 797 ; 1898, 
p. 108. 

Trolldenier. Ibid., 1898, p. 108. 

Locke. Journ. of Phys., xviii., p. 319. 

Ringer. Ibid., xxii., p. xiv. 

Wolf. Ztschr. f. physiolog. Chem., xxvi., p. 442. 

Murray. British Med. Journ., 1900, i., p. 1334. 

Lewin. Deutsch. med. Woch., 1900, p. 689. 

Kurth. Medical Record, 1900, Nov. 10th. 

JRichter. Centralbl. f. Bacteriologie (ii. ), vii., p. 417. 

VI. ZINC. 

The effects of zinc resemble those of copper so closely that they need 
only brief mention. Like copper, the soluble salts form insoluble albu- 
minates and therefor^ possess an astringent action, or in large quantities 
act as irritants and corrosives. The sulphate is the soluble salt most 
commonly used in medicine, but the chloride has frequently given rise 
to corrosive poisoning, and is therefore of greater importance than 
the chloride of copper. The sulphate is much less irritant and more, 
astringent than the chloride, which is used only as a caustic and dis- 
infectant. 

Symptoms. — The sulphate of zinc has a harsh, metallic taste, and in 
small doses causes nausea and vomiting, in larger quantities violent 
vomiting and purging, pain in the abdomen and collapse ; these 
symptoms are due to the local action on the stomach and intestine. 
The insoluble zinc oxide and carbonate are less liable to cause acute 
irritation than the sulphate, but their prolonged ingestion has given 
rise to dyspepsia and constipation or diarrhoea in some cases. The 
continued administration of zinc salts has no effects in man, except 
those of disordered digestion and constipation, and Lehmann could 
detect no effects in the dog, after the administration of 155 G. of the 
carbonate in the course of 335 days, although a considerable amount 
of the metal had been absorbed. 

In workers in zinc, a curious condition known as brassfounders' 
ague, is occasionally met with. It is ushered in by a sense of general 
discomfort and weakness, with more or less pain in different parts of 



ZING. 

the body ; later prolonged rigors and shivering are followed by a rapid 
acceleration of the pulse, coughing and soreness of the chest, and head- 
ache. These symptoms give place to profuse perspiration, and the 
patient sinks into a sleep from which he awakes in ordinary health. 
The attacks may return frequently, and seem to be due to the fumes 
of zinc which escape in the process of casting. A number of obscure 
nervous conditions have also been described as arising from zinc in 
workmen in brass factories and bronze works, but they seem to I 
tremely rare, and it is questionable whether they are really due to the 
zinc or to its impurities, such as arsenic and lead. 

Action. — The general action of zinc can therefore be observed only when 
it is injected intravenously, or hypodermically. For this purpose, the 
double salts alone can be used, as the ordinary salts precipitate the proteids 
of the blood when injected into a vein, and cause acute irritation when ap- 
plied subcutaneously. In the frog, zinc is found to cau.se weakness and 
lessened reflex excitability, and the heart becomes weak and inefficient, ir- 
regular and slow, and eventually ceases in diastole. The action seems to be 
exercised chiefly on the central nervous system and the heart, although the 
voluntary muscles respond more weakly to the electric current in life, and 
lose their irritability entirely soon after death. Meihuizen inferred from his 
experiments that the zinc salts reduce the reflex irritability markedly in 
the frog, but he used an irritant salt and this invalidates his results. 

In mammals the intravenous injection of zinc causes vomiting and diar- 
rhoea, weakness, tremor, and paralysis of the extremities ; and the stomach, 
intestine and heart contain small haemorrhages. The blood-pressure seems 
to be but little affected, until just before death, but the pulse is slowed. 
Helpup found that the subcutaneous injection of zinc salts induced conges- 
tion aud parenchymatous inflammation of the kidney. 

Zinc seems therefore to depress the central nervous system, and to a less 
extent the heart and voluntary muscles, and to cause irritation and conges- 
tion of the mucous membrane of the stomach and intestine, and inflamma- 
tion of the kidney. The fact that vomiting occurs from the intravenous in- 
jection of zinc salts might seem to indicate that it acts directly on the 
medullary centre for vomiting, but may more probably be explained by the 
metal inducing inflammation in the stomach. These effects occur, how- 
ever, only when the metal is administered by way of the blood vessels or 
subcuta neously . 

Zinc has, according to Grahe and Robert, a special affinity for the haemo- 
globin, with which it forms a compound (zinc-haeinol), but its administration 
has no effect on the formation of haemoglobin. 

Lehmanu found that of the zinc absorbed from the stomach and intestine, 
most is contained in the liver and bile, less in the spleen, kidney, thyroid and 
pancreas, and very little in the other tissues. Zinc is excreted by the stom- 
ach and intestinal walls, and in much smaller amounts in the bile and urine. 

Locke found zinc to possess a poisonous action on the tadpole and tubifex 
when present in traces in the water in which they lived, but this effect was 
weaker than that of copper. Richter states that zinc is less poisonous to 
fungi than copper, and very weak solutions seem to promote their growth. 
The zinc salts seem to be in general much weaker than those of copper, which 
they resemble closely in other respects. 

Preparations. 

Zincum(U. S. P.), metallic zinc, is used only to form the other prepara- 
tions and as a reagent. 
Zinci Sulphas (U. S. P., B. P.) (ZnSO, 7H,0), colorless, transparent, 

44 



690 THE HEAVY METALS. 

odorless crystals, with a harsh, astringent, metallic taste, soluble in water, 
not in alcohol. 0.5-2 G. (8-30 grs.), as emetic; 0.05-0.2 G. (1-3 grs.), in 
epilepsy. 

Zinci Oxidum (U. S. P., B. P.) (ZnO), an amorphous white powder with- 
out odor or taste, insoluble in water. 0.1-0.5 G. (2-8 grs.). 

Zinci Carbonas Priecipitatus (U. S. P.), Zinci Carbonas (B. P.), a prepara- 
tion varying somewhat in composition, but always containing some oxide, 
which it resembles in appearance and solubility. 0.1-0.5 G. (2-8 grs.). 

Unguentum Zinci Oxidi (U. S. P.), 1 part to 4 of benzoinated lard. 

Unguentum Zinci (B. P.), 15 per cent, of the oxide. 

Oleatum Zinci (U. S. P.), a yellowish-white mass of the consistency of 
ointment. 

Unguentum Zinci Oleatis (B. P.). 

Zinci Chloridum (U. S. P., B. P.) (ZnCl 2 ), a white powder, or porcelain-like 
mass, irregular, or moulded into pencils, odorless and strongly caustic, very 
deliquescent, and soluble in water and alcohol. 

Liquor Zinci Chloridi (U. S. P., B. P.), about 36 per cent. 

Zinci Acetas (U. S. P., B. P.) (Zn(C 2 H 3 2 ) 2 + 2H 2 0). 0.05-0.1 G. (1-2 grs.). 

Zinci Valerianas (U. S. P., B. P.) (Zn(C 5 H 9 2 ) 2 + 2H 2 0). 0.05-0.1 G. 

Zinci Bromidum (U. S. P.) (ZnBr 2 ). 0.05-0.1 G. 

Zinci Iodidum (U. S. P. ) (Znl 2 ). 0.05-0 1 G. 

Zinci Phosphidum (U. S. P.) (Zn 3 P 2 ). 0.003-0.005 G. 

Zinci Sulphocarbolas (U. S. P., B. P.) (Zn(C 6 H.S0 4 ) 2 + H 2 0), colorless crys- 
tals with an astringent taste, soluble in water and in alcohol. Used exter- 
nally in 1 per cent, solution. (See page 422.) 

Therapeutic Uses. — Zinc sulphate has been used internally as an 
emetic, but not so widely as the sulphate of copper, although it is 
equally efficient. The sulphate, the oxide and the carbonate have been 
advised in the treatment of various brain diseases, such as epilepsy, 
chorea and hysteria, in which zinc is believed to act as a sedative. 
Experiments on animals and on healthy persons give no reason to be- 
lieve in this sedative action, and clinicians are divided as to its useful- 
ness in these diseases, but there is some support for the treatment. The 
oxide and sulphate are seldom employed as astringents in diarrhoea. 

Externally, the zinc preparations, with the exception of the chloride, 
are used as astringents, the sulphate being applied in solution, the 
oxide and carbonate as powders or as ointments, which most prefer to 
the oleate. The oxide is especially useful as an application in many skin 
•diseases. Solutions of the sulphate are used as an eye wash (J per cent.) 
and as an injection in gonorrhoea (1-4 per cent.). In the last case it is 
sometimes formed into a mixture with acetate of lead, the sulphate of 
lead which results being credited with some astringent action and not 
being washed off so readily from the diseased surface. The sulpho-car- 
bolate is also used as a urethral injection, and the salicylate and the 
sulpho-iodolate of zinc have also been introduced as astringent and anti- 
septic applications. 

The chloride of zinc differs from the other salts in being a powerful caus- 
tic, and is used as a paste or in pencil form to destroy malignant growths, or 
in chancres and gangrenous sores. It produces a white eschar and is said to 
be less liable to spread over the surface than potassium, but penetrates the epi- 
dermis with difficulty, and it is therefore advisable to destroy this with potas- 
sium or a blister before applying the caustic. It is sometimes mixed with 
flour or dried gypsum and water to a paste (Canquoin's paste), when a less 



SILVER. 693 

active caustic is desired. Its use is much more restricted at the present 
time than formerly, when there was greater apprehension of the minor surgi- 
cal operations, but it has been recommended as a caustic and disinfectant 
application in inoperable cancer. In very dilute solution it has been applied 
as a disinfectant lotion or injection (1 in 5,000). Burnett's disinfecting solu- 
tion (a somewhat stronger solution than the official liquor) is used to disin- 
fect faeces and urinals, and the liquor of the pharmacopoeia may be employed 
for the same purpose. It has frequently given rise to severe corrosive 
poisoning from being swallowed accidentally or suicidally. 

The acetate of zinc acts in the same way as the sulphate and may be used 
for the same purpose. The valerianate and bromide have been introduced 
with the intention of combining the action of zinc with that of Valerian or 
bromide in hysteria and epilepsy, but valerianic acid is entirely devoid of 
any action on the brain (see Valerian, page 74) and the bromide is given in 
too small doses to exert any influence. The iodide is used in a similar at- 
tempt to combine the astringent effects of zinc and the specific action of 
iodides, but is open to the same objection. The action of the phosphide is 
practically identical with that of phosphorus. Poisoning with zinc is treated 
in the same way as that with copper. 

Bibliography. 

Harnach Arch. f. exp. Path. u. Pharm., hi., p. 53. 

Bueholtz. Ibid., iv., p. 64. 

Helpup. Inaug. Diss., Greifswald, 1889. Deutsch. med. Woch., 1889, p. 782. 

Sacher. Arbeit, a. d. pharrnak. Instit. zu Dorpat, ix., p. 88. 

Grahe. Ibid., ix., p. 155. 

Lehmann. Arch. f. Hygiene, xxviii., p. 291. 

Morner. Ibid., xxxiii., p. 160. 

Jacob). Arb. a. d. k. Gesundheitsamte, xv., p. 204. 

Vblcker. Beitrage z. klin. Chirurg., xxvii., p. 592. 

Richter. Centralbl. f. Bacteriologie (II.), vii., p. 417. 

VII. SILVER. 

The only salt of silver used at all extensively in medicine is the 
nitrate, which is caustic, astringent and antiseptic. Added to solutions 
of proteids, it forms a heavy precipitate of albuminate, which is at 
first white in color but turns darker in the light as the silver is re- 
duced, and which is soluble in the presence of chlorides. Van der 
Does has recently formed a soluble compound of proteid and metallic 
silver which was not coagulated by heat and which failed to putrefy 
after being kept for several weeks. 

Symptoms. — In dilute solution silver is a slight irritant to the skin, 
and causes redness and itching only, but more concentrated solutions 
blister, and the solid nitrate of silver causes an eschar, which is at first 
white, but later turns black from the reduction of the silver in light 
On the mucous membrane, dilute solutions act as astringents, but con- 
centrated cause irritation and corrosion. The caustic action of silver 
does not extend so deeply as that of some other metal-, such as mer- 
cury, because the penetration of the metal is limited by the membrane 
of silver albuminate formed. On the other hand, the silver salts are 
more irritant than those of lead. 

Dilute solutions of silver nitrate are said to contract the V< 
when they are applied locally, and this may be correct under some 



692 THE HEAVY METALS. 

circumstances, but if irritation is induced, the vessels are certainly 
dilated. The astringent action is to be attributed not to any action on 
the vessels, but to the formation of a protective layer of coagulated 
albumin. 

In acute silver poisoning from the ingestion of silver nitrate, the 
symptoms are those of severe gastro-intestinal irritation and corrosion. 
Burning pain is felt in the throat and stomach, and is followed by 
nausea and vomiting and often by purging. The mouth is covered 
with a grayish-white membrane, which turns darker after a time, but 
this is absent if the poison be swallowed in the solid form, as has hap- 
pened sometimes. The corrosion of the stomach and intestine causes 
collapse, with weak pulse, shallow respiration and pinched features, and 
this may be followed by coma, convulsions and death. The throat, 
stomach and intestine presented the ordinary appearances of acute cor- 
rosive poisoning in one case in which an autopsy was performed. 

Action. — The symptoms of acute poisoning are due to the local action, 
and present no features suggesting that silver is absorbed and causes general 
poisoning. The action of silver after absorption has, however, been investi- 
gated in animals poisoned by subcutaneous or intravenous injection. The 
nitrate, owing to its coagulating properties, is unsuitable for this purpose, 
and the hyposulphite of sodium and silver, or a solution of the albuminate 
has therefore been used. In mammals the central nervous system is the 
chief seat of action, especially the medulla oblongata, which seems to be 
stimulated at first, for the blood-pressure rises and the pulse is somewhat 
slow, owing to increased activity of the vaso-motor and vagus centres. 
Later the blood-pressure falls, and the respiration becomes slow and labored, 
and eventually ceases from paralysis of the centre. Gaethgens asserts that 
the diaphragm, and eventually the other striated muscles are paralyzed soon 
afterwards. The heart is comparatively little affected, and often continues 
to beat some time after the respiration has stopped. In less acute poison- 
ing, when the animal survives the injection for several hours or days, a 
marked increase in the bronchial secretion, culminating in oedema of the 
lungs, has been noted ; no satisfactory explanation of this has been advanced, 
but it does not seem due to cardiac inefficiency and occurs also when the 
excised lung is perfused with blood containing silver. Congestion and 
ecchymoses are found in the stomach and intestine, and some authors men- 
tion ulceration of these mucous membranes. Cohnstein found that small 
quantities of silver salts injected intravenously cause some increase in the 
urine for a time, but that larger quantities are followed by albuminuria. 

In cold-blooded animals and in invertebrates, silver preparations are said 
to cause violent convulsions, resembling those of strychnine and followed by 
general paralysis. The heart is, according to one investigator, little affected, 
according to another, it is found in diastole. 

The general action of silver is thus apparently directed first of all against 
the medulla oblongata, the rest of the central nervous system being affected 
to a less extent. The mucous membrane of the stomach and intestine is 
acted on, as by most heavy metals, and the kidney is also liable to irritation. 
(Edema of the lungs occurs frequently. 

Chronic Poisoning. — None of these effects have been observed in 
man, and in fact there is no evidence that in acute poisoning any con- 
siderable amount of the metal is absorbed from the stomach and in- 
testine. When silver is given for prolonged periods, however, some 
is absorbed, although probably only a minute fraction of that actually 



SILVER. 693 

swallowed. In the stomach small quantities of soluble silver salts arc- 
probably changed to the chloride and albuminate, but the form in 
which the metal is absorbed has proved a subject of dispute. It seems 
to be taken up in solution, for none of it is found in the epithelium of 
the stomach and intestine, and some of it may circulate in the blood 
in a soluble form for a short time. But the greater proportion is very 
soon thrown down in the form of miuute granules, which were for- 
merly believed to be metallic silver, but which have more recently 
been said to be one of its organic compounds. The formation of this 
pigment is quite different from the reduction of silver in sunlight, for 
it occurs in complete darkness. The change apparently takes place in 
the cells, especially in the leucocytes, but the granules are afterwards 
extruded into the surrounding fluid. They are found in the connective 
tissues of the body chiefly, and when present in quantity, give a dark 
color to the skin and mucous membranes. This pigmentation (Ar- 
gyria) was much commoner formerly than at the present time, but 
several cases have been described quite recently. The chief source of 
chronic silver poisoning or argyria was formerly the treatment of 
epilepsy with the nitrate. It has also arisen locally from the pro- 
longed use of silver nitrate solution as an application to the eye, throat, 
and vagina, and occurs in the workers in artificial pearls, who use 
silver as a pigment. 

The deposit of the silver in the skin gives it a darker color, varying 
from light gray in mild cases to a darker slate shade after more pro- 
longed use. It is generally distributed all over the body, but in some 
cases has been especially marked in the face, and it is said to begin in 
the gums, where it causes a dark, slate-colored line somewhat resem- 
bling the lead line. In the skin it is found in the corium, not in the 
epidermis. The deposit and the dark color extend throughout the 
alimentary canal and the respiratory passages, the granules occurring 
in the connective tissue, particularly in the intestinal villi, and not in 
the epithelium. The glomeruli of the kidneys, the connective tissue 
of the liver and spleen, the choroid plexus, the tunica intima of the 
aorta, the serous membranes, and the mesenteric lymph glands contain 
more of the deposit than other organs. The pigmentation is not ac- 
companied by any other symptom of importance, and the victims live 
to old age without suffering from the chronic poisoning in any way, 
except from the annoyance induced by the change in color. 

Local argyria is sometimes met with from the prolonged application 
of silver nitrate to the eye or throat, when it tints the eyelids and 
mouth, and from working with silver, when the hands are permanently 
blackened from the granules being forced into the skin. 

Argyria is quite incurable, although many attempts have been made 
to remove it. Iodide has been tried, for the most part without effect, 
and blistering is equally valueless as the pigment lies deeper than the 
epidermis. The only known solvent of the granules is cyanide of 
potassium, and of course this is inadmissible owing to its powerful 
poisonous action. 



•694 THE HEAVY METALS. 

Argyria has been induced in animals by prolonged treatment with 
small doses of silver salts, though the pigment is not found in the skin 
in them, but in the duodenal mucous membrane and the mesentery 
attached to it, the mesenteric lymph glands, the spleen and liver. A 
still more limited area of argyria has been caused in animals recently 
by administering for a few weeks the glycyrrhizinate of silver. It is 
not unlikely that more prolonged administration would lead to other 
organs and perhaps the skin being involved. A deposit of silver pig- 
ment has also been induced in animals by a single injection of a non- 
irritant preparation into a vein, or into the subcutaneous tissue. Here 
the silver is found at first in the liver capillaries, the glomeruli of the 
kidney, the intestine and the bone marrow, but is afterwards taken up 
by the leucocytes, and carried to all the organs of the body. Various 
symptoms of chronic poisoning quite apart from argyria have been de- 
scribed in animals from prolonged treatment with silver, but it would 
seem that they were due not to the direct action of the drug, but to the 
continued irritation of the stomach and intestine, as they were entirely 
absent when less irritant preparations and greater care in administra- 
tion were used. 

In man it seems likely that most of the silver passes through the 
alimentary canal unabsorbed, and that the small proportion taken up 
by the tissues is precipitated and remains embedded in them indefi- 
nitely, for the pigmentation remains unchanging in its depth, and there 
is therefore no reason to suppose that any of the silver is eliminated. 

In animals, however, some of the silver injected hypodermically or 
intravenously is excreted by the epithelium of the alimentary canal. 
None appears in the urine. In the frog, silver injected hypodermically 
is all excreted by the epithelium of the tongue, is swallowed, and 
passes out in the faeces. No other poison is known to be eliminated 
by this channel. 

Silver nitrate is a powerful antiseptic, partly from its action in co- 
agulating the proteids of the micro-organisms, partly from the specific 
effects of the metal, as is shown by the fact that the albuminate of sil- 
ver is also an active disinfectant. 

Preparations. 

Argenti Nitras (U. S. P., B. P.) (AgN0 3 ), colorless crystals which be- 
come gray or grayish -black on exposure to light in the presence of organic 
matter, with a bitter, caustic, strongly metallic taste, very soluble in water, 
less so in alcohol. 0.01-0.03 G. (£- ^ gr.) in pills made up with kaolin. 

Argenti Nitras Fitsus (U. S. P.), moulded nitrate of silver, lunar caus- 
tic — a white, hard solid, generally cast in the form of pencils. 

Argenti Nitras Indurattjs (B. P.), toughened caustic, a silver nitrate 
fused with 5 per cent, of nitrate of potassium. 

Argenti Nitras Dilutus (U. S. P.), Argenti Nitras Mitigatus (B. P.), miti- 
gated caustic, consists of one part of nitrate of silver and two parts of nitrate 
of potassium fused into rods like lunar caustic. 

Argenti Iodidum (U. S. P.) (Agl), a heavy, amorphous, yellow powder, 
insoluble in water or alcohol. 

Argenti Oxidum (U. S. P., B. P.) (Ag 2 0) ; a heavy, brownish-black powder. 



SILVER. 

odorless and having a metallic taste, very little soluble in water. 0.03-0.1 
G. Q-2 grs.). 

The silver preparations ought to be kept in dark amber-colored battles, in 
order to prevent their being reduced by light, and ought not to be prescribed 
with organic matter, which rapidly reduces them. 

Therapeutic Uses. — Silver nitrate pills have been recommended in 
some forms of dyspepsia and vomiting, and in gastric ulcer, and have 
also been used as astringents in diarrhoea, but generally with little 
benefit. A very ancient use of silver oxide, and more recently of the 
nitrate, is that in the treatment of epilepsy, chorea, tabes and various 
other nervous diseases. This dates from the. Arabs, and is said to 
have originated from the astrological medicine of that period, which 
taught that nervous diseases were especially affected by the phases of 
the moon, which was associated with silver in their system (hence, 
lunar caustic, lunacy). Clinical experience shows that silver is of no 
benefit in epilepsy, and, in fact, it is improbable that silver reaches the 
central nervous system in any other form than inert granules. This 
use of silver very often gave rise to argyria without benefiting the pa- 
tient, about 15-30 G. proving sufficient to cause marked pigmentation. 

Externally, silver nitrate is employed very extensively, the sticks of 
lunar caustic being used to destroy warts and other small skin growths, 
to arrest capillary haemorrhage, to destroy the false membranes of 
diphtheria, and for other similar purposes. Where a milder caustic is 
required the mitigated caustic is used instead of ordinary lunar caus- 
tic. A solution of 2-5 per cent, may also be applied to cauterize chan- 
cres and indolent ulcers, and one of 1—2 per cent, may be painted on 
mucous membranes as an irritant antiseptic. A solution of common sal t 
is then used to wash the part, in order to remove the excess of silver. 
In ophthalmia, especially of the infectious form, a solution of 1—2 per 
cent, is extremely valuable, and, in fact, a routine treatment in some 
lying-in hospitals is to wash the eyes of the infant with this solution 
immediately after birth as a prophylactic measure to prevent oph- 
thalmia. A solution of this strength is only to be used by the sin 
himself, and the eye should be washed out with a salt solution at 
once. A more dilute solution (\-\ per cent.) may be used as a lotion 
for the eye more frequently, may be applied to extensively denuded 
surfaces, as burns, and is often thrown into the rectum in chronic 
dysentery. In gonorrhoea the nitrate of silver, one part in 500-2000 
of water, is used as an injection, and is found to have great value, de- 
stroying the gonococci and promoting healing. Very much stronger 
solutions (up to 5 per cent.) have been used to abort the disease in Its 
onset, but cause great pain. 

The precipitation of silver nitrate by proteids and chlorides confine^ Ml 
disinfectant action to narrower limits than those of some other ■atiseptioB, 
and this has led to the introduction of a number of other compounds, \\ biefc 
are less easily dissociated and accordingly less liable to be thrown out of BC- 
lution. Thus argentamine, a ten per cent, solution of silver phosphate in 
ten per cent, ethylendiamine solution, has been used in gonorrhoea dilated 
to 1:1,000-5,000, in the eye in five per emit, solution. It pUMItHtOS beHSI 



696 THE HEA VY METALS. 

than silver nitrate, but the alkaline diamine renders it somewhat irritating. 
Another recent product is argonin, which is a combination of casein and 
silver, is soluble in water, and, like argentamine, is not precipitated by 
chlorides nor by albumin ; it is a somewhat weaker antiseptic than the nitrate 
and argentamine. The lactate of silver, actol, and the citrate, Urol, have 
also been used as antiseptics. Actol is soluble in water, and resembles the 
nitrate in coagulating proteids, while itrol, on the other hand, is practically 
insoluble (1 to 3,800 water). The former is used in solution ($ per cent.), the 
latter as a disinfecting powder in wounds. Actol and argonin have been 
shown to have very considerable disinfectant power in test-tube cultures, and 
actol lessens the putrefaction in the bowel and constipates to some extent, 
but argonin has no effect on the intestinal microbes. Protargol and largin, 
proteid compounds of silver, have been introduced lately, and still more re- 
cently Crede has advised the use of soluble metallic silver in water or in oint- 
ment. These have all been reported on favorably as antiseptics in urethral 
infection and similar conditions, but the earlier claims of their advocates 
that they were of value as antiseptics in constitutional diseases have proved 
to have no more foundation than the similar statements in regard to other 
antiseptics. (See pages 393-396.) 

Silver preparations ought not to be used for long periods, as argyria has 
been induced in three months and after the use of 15-30 G. (£-1 oz.) of the 
nitrate. 

In cases of poisoning with silver nitrate, eggs, milk and, above all, com- 
mon salt solution are indicated to form insoluble compounds. In argyria 
no improvement can be expected, though the iodide of potassium may be 
tried. 

Bibliography. 

Bogoslowsky. Virchow's Arch., xlvi., p. 409. 

Huet. Journ. de l'Anat. et Physiol., 1873, p. 408. 

Rouget. Arch, de phys., 1873, p. 333. 

Jacobi. Arch. f. exp. Path. u. Pharm., viii., p. 198. 

Rozsahegzi. Ibid., ix., p. 289. 

Cohnstem. Ibid., xxx., p. 129. 

Loew. Pfliiger's Arch., xxxiv., pp. 596, 602. 

Schubert. Zts. f. Heilkunde, xvi., p. 341. 

Samojloff. Arb. a. d. pharm. Instit. Dorpat, ix., p. 27. 

Gerschun. Ibid., x., p. 154. 

Tschisch. Virchow's Arch., c, p. 147. 

Crede. Arch. f. klin. Chirurg., lv., p. 861. 

Mosse. Zts. f. phys. Chem., xxiii., p. 160. 

Liebrecht. Therap. Monatsheft, 1895, p. 306. 

Van der Does. Zts. f. phys. Chem., xxiv., p. 351. 

Athanasiu. Journ. de Physiol., iii., p. 163. 

VIII. BISMUTH. 

The insoluble salts of bismuth, in especial the subnitrate, have long 
enjoyed a reputation in the treatment of gastric and intestinal irrita- 
tion, and have more recently been advised in surgery as applications 
to granulating wounds. 

Symptoms. — Taken in therapeutic doses, the subnitrate induces no 
marked symptoms, even after prolonged use. It has little or no taste, 
and passes through the stomach and intestine for the most part unab- 
sorbed. It is said to increase the peristalsis of the stomach and the 
secretion of mucus, but it may be questioned whether it has more effect 
here than any other heavy powder. In the intestine it is said to have 
some effect in increasing the leucocytes of the blood, and often causes 



BISMUTH. 097 

some constipation. It gives the stools a black color, which is gener- 
ally believed to be due to the formation of the sulphide of bismuth, 
but which Quincke ascribes to the reduction of the subnitrate in the 
intestine. 

Very little of the bismuth swallowed is absorbed, but several au- 
thorities have found traces in the urine of patients treated with it in- 
ternally so that some evidently passes into the blood under certain 
unknown conditions. Enormous quantities have been administered 
internally without any symptoms of poisoning being elicited, but in one 
or two cases some stomatitis has been remarked, while in other in- 
stances large concretions of bismuth have been found in the stomach 
and bowel. Some of the older writers describe serious poisoning from 
bismuth, but this was not due to the drug itself, but to the lead, arsenic, 
or antimony with which it was contaminated. 1 As long as bismuth 
was given only internally, no serious symptoms arose from its action, 
and in fact any effects whatever beyond slight constipation were ex- 
tremely rare. But since its use was extended to wounded surfaces, 
several cases of serious intoxication have occurred. The symptoms 
are salivation, swelling of the gums, tongue, and throat, pain and 
difficulty in swallowing, black spots in the mouth and throat, and gan- 
grene of the soft palate and other parts of the mucous membrane of the 
mouth. Vomiting, diarrhoea and albuminuria follow, but the pa- 
tients generally recover when the dressing is removed from the 
wound. In these cases much less bismuth is applied than is often 
prescribed for internal use, so that it would appear that it is absorbed 
more rapidly from granulating surfaces than from the mucous mem- 
branes, or that what is absorbed from the stomach and intestine is 
prevented by the liver from reaching the general circulation. 

Action. — The general action of bismuth has been studied in animals 
by the subcutaneous or intravenous injection of the double salts, such 
as the tartrate of bismuth and sodium. In frogs, the symptoms are 
those of stimulation of the spinal cord and medulla oblongata, followed 
by depression and paralysis. The stimulation induces tonic convul- 
sions, which are separated by periods in which the frog is at first ap- 
parently normal, but in which symptoms of depression and paralysis 
appear later. The peripheral nerves and muscles and the heart are 
little affected. 

In mammals also, large doses act chiefly on the central nervous 
system. The respiration is accelerated, the heart slowed, and violent 
clonic and tonic convulsions follow at short intervals, during which the 
movements are weak and incoordinated. Towards the fatal issue of the 
injection, the heart often ceases entirely for some time, and then regains 
its former rhythm quite suddenly. The blood-pressure falls, partly 
owing to the weakness of the heart, partly from depression of the vaso- 
motor centre. In some animals, the respiration ceases before the heart ; 

^symptom formerly noted in cases treated with bismuth was an extremely dis- 
agreeable odor in the breath, but this lias been shown to be due to the preset] 

tellurium in the preparation. 



698 THE HEAVY METALS. 

in others, the sequence is reversed. The heart seems to be affected 
directly, for division or paralysis of the vagus nerves docs not alter 
the effects. 

Smaller quantities injected intravenously or subcutaneously into 
mammals induce a more chronic form of intoxication, which resembles 
that seen in man. The earliest symptoms are loss of appetite, vomit- 
ing and diarrhoea, salivation and stomatitis with ulceration of the gums, 
tongue and buccal mucous membrane. Weakness, slowness and inco- 
ordination of the movements follow, and except in very chronic cases, 
tetanic convulsions occur at intervals. The urine contains albumin 
and casts. The weakness gradually deepens into complete paralysis, 
and the animal dies, generally without convulsions. The heart seems 
little affected in the chronic intoxication, but the blood-pressure is low 
from the intestinal irritation and general collapse. 

Besides the stomatitis and ulceration of the mouth, the post-mortem 
appearances in chronic bismuth poisoning in animals consist in some 
congestion, inflammation and necrosis in the kidney, and an intense 
black coloration of the caecum and the upper part of the large intes- 
tine. This pigmentation is limited very exactly by the ileocaecal 
valve, and extends throughout the thickness of the bowel wall. The 
mucous membrane may also be necrosed in places, and ulcers and 
haemorrhages are met with in it. The black coloration is due to a 
deposit of bismuth sulphide on the mucous membrane, and in the 
capillary vessels and lymph spaces. Meyer and Steinfeld found that 
bismuth is excreted all along the alimentary canal, but in larger quan- 
tities in the caecum and large intestine than elsewhere, and they 
ascribe the ulceration to the precipitation of the sulphide in the 
vessels and the consequent arrest of the blood-current. When sul- 
phide solution was artificially introduced into the stomach and small 
intestine, bismuth caused necrosis and ulceration here also, so that 
there is considerable support for this view. 

They found bismuth to be stored in considerable quantity in the liver, 
and to be excreted by the urine, stomach and intestine, but especially 
by the caecum and large bowel. It has been found in the saliva by 
other observers, and perhaps in traces in the milk, although the last is 
not satisfactorily established. 

The action of bismuth in acute poisoning in animal experiments 
seems therefore to be exerted on the medulla and spinal cord, to a less 
extent on the heart, while in chronic intoxication the organs affected 
are those by which it is excreted — the mouth, kidney, large intestine 
and caecum. 

Preparations. 

Bismtjthi Subnitras (U. S. P., B. P.), white bismuth, Magisterium Bis- 
muthi, bismuth oxynitrate, a heavy white powder odorless and almost taste- 
less, insoluble in water or alcohol but soluble in nitric or hydrochloric acid. 
It consists of a mixture of the hydrate and subnitrate of bismuth in -varying 
proportions. 1 0.3-2 G. (5-30 grs.), in powder or suspended in water. 

1 The B. P. defines this preparation as bismuthoxynitrate (BiON0 3 H 2 0), but some 
hydrate is almost invariably present. 



BISMUTH. 

Bismuthi Subcarbonas (U. S. P.), Bismuthi Carbonas (B. P.), bismuth oxy- 
car Donate, a white or pale yellowish-white powder, varying in composition, 
odorless, tasteless, insoluble in water or alcohol. 0.3-2 G. (5-30 grs.) in 
powder. 

Trochiscus Bismuthi Composites (B. P.) ; each contains 2 grs. of bismuth 
oxycarbonate along with the carbonates of magnesia and of lime. 

Bismuthi Salicylas (B. P.), the salicylate or oxysalicylate of bismuth, is a 
white, amorphous powder, insoluble in water. 5-20 grs. 

Bismuthi Oxidum (B. P.) (Bi 2 O s ), a slightly brownish-yellow powder, in- 
soluble in water. 5-20 grs. 

Bismuthi Citras (U. S. P.) (BiC fi H 5 0.), a white powder, odorless, tasl 
insoluble in water or alcohol, used only to form 

Bismuthi et Ammonii Citras (17. S. P.), small, shining, translucent .-< 
odorless, but with a slightly acidulous and metallic taste, and becoming 
opaque on exposure to the air, very soluble in water, less so in alcohol. 0.1- 
0.3 G. (2-5 grs.). _ 

Liquor Bismuthi et Ammonii Citratis (B. P.) contains the equivalent of 5 
per cent, of bismuth oxide. J-l fl. dr. 

Therapeutic Uses. — Bismuth has been used chiefly in gastric catarrh 
and ulcer, and has often been looked upon as a specific in the last 
affection, though it acts simply as a protective powder with perhaps 
some astringent properties. It has been found that when swallowed 
it is at first deposited in the most dependent part of the stomach, but 
is later distributed evenly over the surface, and forms a continuous 
sheet over any ulceration, which it thus protects from mechanical injury 
from the food, and also from the chemical action of the gastric juice. 
The subnitrate is the only one of the official preparations largely used 
for this purpose, and is generally administered in quantities of 2-3 G. 
(30-45 grs.) per day in powder. Recently the use of much larger 
quantities (10—15 G., 150—250 grs., per day) has been recommended. 
Bismuth has also been used in diarrhoea for its astringent and protective 
action on the intestine, which is again due to its being deposited on the 
mucous membrane and acting as a mechanical coating over irritated 
surfaces. 

The subnitrate has been advised in surgery as an antiseptic, astrin- 
gent powder to replace iodoform. It is true that it is devoid of the 
disagreeable odor of the latter, but it is not a harmless remedy, as wa- 
at first supposed, for several cases of bismuth poisoning have been 
recorded from its surgical use. Like iodoform, its value depends not 
so much ou its germicidal action as on its absorption of the fluids of 
the wound, which renders the surface less suitable for the growth of 
bacteria. The therapeutic uses of the bismuth preparations then are 
largely due to their insolubility. The subnitrate is generally used, the 
carbonate less frequently, while the soluble double citrate is quite 
superfluous. 

Several new compounds of bismuth have been introduced into therapeutics 
of late years, chiefly with the intention of combining the astringent prop- 
erties of bismuth with the antiseptic action of benzol preparations. Among 
these may be mentioned the salicylate (B. P.) and bcnzoatc. which have been 
used as intestinal antiseptics and astringents. (0.2-0.3 G. f& 6 
powder.) Others are dermatol (gallate of bismuth. C.H ,(OH) s COOBiO), aim! 



700 THE HEAVY METALS. 

(bismuth oxyiodide gallate), thioform (bismuth dithio-salicylate), bismuth 
phenolate, cresolate, orphol (/^-naphtolate), xerqform (tribromphenolate), (an- 
nate, sulphocarbolate, dermol (chrysophenate), eudoxin (tetraiodo-phenolphtalei- 
nate). These have been used chiefly as cutaneous applications in various 
forms of skin disease, in which an astringent and protective powder is indi- 
cated, in burns and ulcers, in some ophthalmic conditions, and as dusting 
powders after operations. Several of them, such as dermatol (0.1-0.2 G.), 
and the phenolate, cresolate, naphtolate, and tribromphenolate (1-4 G.), 
have been advised as intestinal antiseptics and astringents, and the last four 
have been shown to be decomposed in the intestine into bismuth and the 
corresponding aromatic antiseptic. Stomatitis and other symptoms have 
been observed occasionally from the external application of these new com- 
pounds, but they seem less dangerous than the subnitrate in ordinary sur- 
gical use. The phenol, cresol, and other similar substances freed by the 
decomposition of these new compounds, might also give rise to symptoms of 
poisoning, if large quantities were rapidly formed in the intestine. Derma- 
tol has no effect on the double sulphates of the urine, so that it apparently 
does not act as a germicide, but merely as an astringent protective in the 
intestine. 

Bibliography. 

Meyer u. Steinfeld. Arch. f. exp. Path. u. Pharm., xx., p. 40. 

Dalche and Villejean. Arch. gen. de Med., 1887, ii., p. 129. 

Jasenski. Arch, des Sciences biolog. , ii. , p. 247. 

Surveyor and Harley. Brit. Med. Jour., 1895, ii., p. 1483. 

Fleiner. Centralbl. f. klin. Med., 1893, p. G9 (supplement). 

Malthes. Centralbl. f. inn. Med., 1894, p. 2. 

Cramer. Munch, med. Woch., 1896, p. 587. 

Heinz. Berl. klin. Woch., 1892, p. 1190. 

Kocher. Volkmann's Klinische Vortriige, No. 224. 

Petersen. Deutsch. med. Woch., 1883, p. 365. 

Savelieff. Therapeut. Monatsh., 1894, p. 485. 

Cerium. 

Cerium is used to a limited extent in therapeutics in the form of the 
oxalate. Very little is known of its effects, but it is apparently absorbed 
with difficulty from the stomach and intestine. It is said to depress the 
heart, and to induce vomiting and purging, with hyperemia and ecchymoses 
in the stomach and bowel, and nephritis and congestion in the kidney, when 
it is injected into the blood vessels. 

In therapeutics it is used in vomiting from seasickness, pregnancy and 
other conditions, in which irritation of the stomach is not the primary cause. 
It is quite unknown how it acts in these cases, but it is surmised that its ef- 
fects are local and similar to those of bismuth subnitrate. 

Cerii Oxalas (U. S. P., B. P.) (Ce 2 (C 2 4 ) 3 +9H 2 0), a white granular powder, 
tasteless, odorless, insoluble in water or alcohol. 0.1-0.6 G. (2-10 grs.). 

IX. ALUMINIUM AND ALUM. 

The chief pharmacopoeial preparation of aluminium is the sulphate of 
aluminium and potassium, or alum, which has been largely used for its 
astringent properties. Alum solutions precipitate albumin, but the 
precipitate is soluble in excess of the proteid. It is not known 
whether an albuminate is formed similar to those of the heavy metals, 
though it seems probable that this is the case. Dilute solutions of alum 
have an astringent effect from their throwing down a layer of precip- 
itated proteid on the surface of the mucous membranes or on wounded 
surfaces, but larger quantities and more concentrated solutions act as 






ALUMINIUM AND ALUM. 701 

irritants. This is more especially the case when dried alum is applied, 
for, in addition to its coagulating effect on the proteids, this prepara- 
tion has a great avidity for water. 

Symptoms. — Alum solutions have a sweetish, astringent taste, and in 
small quantities induce no symptoms except a feeling of dryness and 
astringency of the mouth and throat, and some constipation. Larger 
doses act as gastric irritants and cause nausea and vomiting, and, in 
extreme cases, purging. Even the largest quantities, however, are 
followed by no symptoms except those of gastro-intestbal irritation 
and inflammation, and the long-continued use of alum does not elicit 
any symptoms of chronic poisoning. The aluminium salts are not ab- 
sorbed in any quantity from the stomach and intestine, so that do 
symptoms of general poisoning arise from the internal use of the salt. 
Aluminium vessels may be used for cooking, or even to contain acid-, 
without danger of intoxication, as has been shown by a recent series 
of investigations. 

No case of aluminium poisoning presenting the symptoms of gen- 
eral intoxication has been recorded as yet, but if the newer prepara- 
tions are used as extensively and negligently as some of the other 
modern panaceas, medical literature will probably be enriched by such 
additions in the near future. 

Aluminium salts, especially the acetate, chloride and some more 
recent preparations, have very considerable antiseptic power, much 
more than some of the more generally used antiseptics, such as boric 
acid. 

Action. — Aluminium has a very remarkable general action when it 
obtains access to the blood. In Siem's experiments on animals, the sodium- 
aluminium lactate or tartrate induced a very slow intoxication, mammals 
never dying from the effects sooner than one or two weeks after the in- 
travenous injection of the salts. In frogs the symptoms were those of a de- 
scending paralysis of the central nervous system, the heart and the peripheral 
nerves and muscles being little affected. In mammals the first symptoms 
appeared only after three to five days, and consisted in constipation, rapid 
loss of weight, weakness, torpor and vomiting; marked abnormalities in 
movement and sensation were observed later, such as tremor, jerking 
movements, clonic convulsions, paresis of the hind legs, anesthesia of the 
mouth and throat, and lessened sensation all over the body. Before 
death, diarrhoea often set in, and albuminuria was generally present. 
The mucous membrane of the stomach and bowel was found swollen and 
congested, the kidney and liver had often undergone fatty degeneration, 
and haemorrhages were found in the renal cortex. Aluminium was found in 
the urine. 

Like the other members of the heavy metal series, aluminium therefore 
acts on the bowel and kidney in general poisoning, while many of the symp- 
toms point to a direct action on the brain. Dollken has recently confirmed 
Siem's results, and showed that the nerve cells and fibres el* the cord and 
medulla undergo degeneration, particularly those of the lower cranial nerves. 

It has been stated that the alum salts of the food are absorbed and stored 
in the bones, but this is incorrect. AVhat little is absorbed is probably rap- 
idly excreted by the bowel and perhaps by the urine. 

A metal which is very nearly related to aluminium in its effects in the 
organism is Beryllium. It differs chiefly in being more poisonous, In being 



702 THE HEAVY METALS. 

absorbed from the stomach and intestine, and in causing more distinct lesions 
in these when it is injected into the blood. 

Preparations. 

Alumen (U. S. P., B. P.), alum, potassium alum, (Al 2 K 2 (SOJ 4 + 24H 2 0), 
large, colorless, octahedral crystals, with a sweetish, strongly astringent 
taste, soluble in water, but not in alcohol. 0.3-1 G. (5-15 grs.). 

Glycerinum Aluminis (B. P.), 10 per cent. 

Alumen Exsiccatum (U. S. P.), Alumen Ustum (B. P.), burnt alum, dried 
alum (A1 2 K 2 (S0 4 ) 4 ), a white, granular powder, attracting moisture on ex- 
posure to air, soluble in water. 

Alumini Hydras (U. S. P.) (Al 2 (OH) 6 ), a white, light, amorphous powder, 
odorless, tasteless, insoluble in water or alcohol, but soluble in hydrochloric 
or sulphuric acids and in fixed alkalies. 0.3-1 G. (5-15 grs.). 

Alumini Sutyhas (U. S. P.) (A1 2 (S0 4 ) 3 ), a white, crystalline powder, with a 
sweetish, astringent taste, soluble in water, not in alcohol. 

Uses. — Alum is used chiefly externally for its astringent properties. 
It has been employed as an emetic, but is less reliable than the sul- 
phate of copper or tartar emetic, and very large doses (4-8 G., 1-2 
drs.) are required. In diarrhoea either alum or the hydrate is some- 
times advised. 

Alum solution is useful as an astringent gargle (1—5 per cent.), as 
an injection in gonorrhoea (J— 1 per cent.), as an astringent lotion in 
skin diseases (1 per cent.), and for other similar purposes. It is said 
to tend to cause corneal perforation by dissolving the intercellular sub- 
stance, but has been used in ophthalmia by many surgeons. Dried 
alum is more caustic, from its withdrawing fluid from the tissues. It 
has been used to a limited extent as an emetic ; more frequently as an 
application to exuberant granulations, haemorrhoids, or condylomata, 
and as a styptic in bleeding from the nose or teeth. Alum has often 
been prescribed in chronic lead poisoning with success. A one per 
cent, solution has been injected into the rectum in chronic dysentery, 
but is inferior to the nitrate of silver. 

A large number of aluminium preparations have been introduced recently 
as antiseptic astringents. Among these may be mentioned alumnol (naph- 
tol sulphonate of aluminium), salumin (salicylate), tannal (tannate), gallal 
(gallate), boral (boro tartrate), cutol (borotannate), alsol (acetate), alkasal 
(salicylate of potassium and aluminium). They are used partly in solution, 
chiefly as dusting powders, but it has yet to be proved that they are supe- 
rior to the older preparations. As with so many of the products of the new 
industrial chemistry, they are thrown on the market in such profusion, and 
are heralded with such exaggerated praise, that it is impossible at present to 
state which of them are really improvements on the more generally recog- 
nized preparations, and which are merely adapted to enrich the inventor, 
without materially advancing therapeutics. 

Bibliography. 

Siem. Inaug. Diss., Dorpat, 1886. 
Dollken. Arch. f. exp. Path. u. Pharm., xl., p. 98. 
Jalandela Croix. Ibid., xiii., p. 210. 
Heinz. Berl. klin. Woch., 1892, p. 1158. (Alumnol.) 

Plagge u. Lebhin. Ueber Feldflaschen imd Kochgeschirre aus Aluminum, Berlin, 
1893. 



GOLD AND PLATINUM. 703 

X. MINOR METALS. 
Gold. 

Gold has never been largely used in therapeutics, although repeated at- 
tempts have been made to introduce it in the treatment of the most diverse 
conditions ; the salt employed has almost invariably been the double chlor- 
ide of gold and sodium. It is much less poisonous than many of the other 
metals and may be taken for many months without entailing any untoward 
symptoms. The subcutaneous injection in frogs is followed by paral; 
the central nervous system, gold possessing little action on the heart aiid 
striated muscles in these animals. Injected intravenously in dogs, it causes 
vomiting and dyspnoea, which soon pass off, but if sufficient has been in- 
jected the animal suffers from nausea, vomiting and diarrhoea for several 
days, eats nothing, loses flesh rapidly, and dies a week or more after the ex- 
periment. Numerous ulcers are found in the stomach and intestine, and 
these often betray their presence in life by haemorrhages. Gold lowers the 
blood pressure somewhat on intravenous injection, probably from the dila- 
tion of the mesenteric vessels accompanying the intestinal action. It has 
little effect on the rate of the heart except in large doses, and dilates the 
vessels when perfused through them. When given by the mouth to dogs 
and cats, it is at once ejected from the stomach by vomiting. 

Gold has therefore the ordinary general effects of the heavy metals in 
causing acute irritation and ulceration of the alimentary canal. The early 
vomiting may be due to action on the centre, but is more probably caused 
by its irritating the stomach. The diarrhoea, and the ulceration of the 
stomach and intestine probably indicate that it is excreted by these organs. 

Auri et Sodii Chloridum (U. S. P.), a mixture of equal parts by weight of 
dry gold chloride (AuCl 3 ) and sodium chloride (NaCl), an orange-yellow 
powder, with a saline, metallic taste, deliquescent in the air and very solu- 
ble in water. 0.005-0.03 G. (to~2 g 1 '-), m solution. Gold has been used in 
various nervous disorders, in particular in those of a hysterical nature, and 
may conceivably be of value through suggestion, if the patient be informed 
of the nature of the remedy. It has also been advised in syphilis, rheuma- 
tism, and other chronic diseases. Of late years it has been widely adver- 
tised as a specific in chronic alcoholism, but analysis has shown that no gold 
was contained in the fluid advocated, and there is no reason to suppose that 
it is of value except by means of suggestion. Kantnack and Calmette have 
recommended its hypodermic injection in cases of snake bite. 

Bibliography. 

Aronowitsch. Inaug. Dissertation, Wurzburg, 1881. 
Schultz. Inaug. Dissertation, Dorpat, 1892. 

Platinum. 

Platinum resembles gold in its action very closely, but is much more poi- 
sonous. In the frog it paralyzes the central nervous system, and later the 
striated muscles. Kebler observed a stage of convulsions precede that of 
paralysis, the spasms evidently arising from the spinal cord or medulla 
oblongata. In mammals the symptoms resemble those of gold poisoning in 
almost every detail. Small quantities of platinum donble salts injected in- 
travenously increase the urine to some extent ; larger injections cause albu- 
minuria. 

Platinum was at one time advised in syphilis, but has never been widely 
Used. 

Bibliography. 

Kebler. Arch. f. exp. Path. u. Pharm., ix., p. 137. 
Cohnstein. Arch. f. exp. Path. u. Pharm., zzx., p. 127. 



704 THE HEAVY METALS. 



Chromium. 



Chromium is used in medicine in the form of chromic acid and the bichro- 
mate of potassium, which are both powerful oxidizing bodies in addition to 
their poisonous action as metallic oxides. The former property renders 
them more irritant and corrosive than most of the salts of the heavy metals. 
Chromic acid in particular is a powerful caustic, combining the action of a 
metallic oxide, an acid, and a strongly oxidizing agent. Applied to the skin 
in substance it corrodes it, but is said to cause less pain than the more pene- 
trating caustic potash. Even in dilute solution the chromic salts and the 
acid act as skin irritants, and the caustic effects are shown by s-kin diseases, 
and particularly by deep perforating ulcers in persons exposed constantly to 
the dust of chromic salts in factories. These ulcers arise from any abrasion 
of the skin, while the acid does not seem to be capable of penetrating the 
unbroken epidermis. The cartilaginous septum of the nose is also a common 
seat of ulceration, which eventually leads to perforation. These ulcers arise 
from the local action of the poison and not from its absorption ; they are said 
to be almost painless. The inhalation of the dust leads to chronic bronchitis, 
while that swallowed and absorbed may give rise to nephritis. 

Symptoms. — In acute poisoning, when a large quantity of the acid or of a 
salt is swallowed, the symptoms are those of gastro-intestinal corrosion, in- 
tense pain in the throat and stomach, vomiting and purging, with blood in the 
vomited matter and the stools, collapse and frequently death. The mouth 
and throat are stained yellow, and the stomach and intestine exhibit the 
usual appearance of violent corrosive poisoning. 

The general action of chromic preparations may be elicited in animals by 
subcutaneous or intravenous injection, or by the administration of smaller 
quantities by the mouth. The symptoms resemble those caused by the gen- 
eral action of other metals. In the frog increasing weakness, tremor and 
eventually paralysis of the central nervous system are induced. In the 
mammal weakness and slowness in the movements is followed by albumi- 
nuria and later by diarrhoea and vomiting. Sometimes twitching of the 
muscles or even convulsions are seen, and then the weakness passes into 
general paralysis. The heart seems little affected by chromium, but the 
blood-pressure falls. After death the stomach and bowel are found con- 
gested, and the mucous membrane is necrosed and ulcerated in some parts, 
covered with ecchymoses in others. Haemorrhages are also found in other 
organs of the body, notably in the heart wall. The kidney is in a state of 
acute parenchymatous nephritis and often contains deposits of uric acid, and 
albumin, casts, and often blood cells appear in the urine. In chronic poison- 
ing interstitial nephritis is said to occur. 

Chromic acid and its salts are readily absorbed from the stomach and in- 
testine. They seem to be excreted for the most part through the kidney, to 
a less extent by the intestinal epithelium probably. In the urine the metal 
occurs in part in organic combinations. 

Chromic oxide compounds act in the same way as the chromates, but are 
much less poisonous. 

Preparations. 

Acidum Chromicum (U. S. P., B. P.), chromic acid or anydride (Cr0 3 ), forms 
crystals of dark purplish-red color and metallic lustre, odorless, very soluble 
in water. When brought in contact with organic substances, such as alco- 
hol, glycerin or sugar, it oxidizes them rapidly and often violently with ex- 
plosion. 

Liquor Acidi Chromici (B. P.), 25 per cent. 

Potassii Bichromas (U . S. P., B. P.), bichromate or dichromate of potassium 
(K 2 Cr 2 7 ), forms large, orange-red transparent crystals, with a bitter metal- 
lic taste, soluble in ten parts of water. 6-12 mgs. (ro~i g r )- 

Chromic acid is used as a caustic application to malignant growths, 



MANGANESE. 705 

chancres and diphtheritic membranes, to a less extent as an irritant antisep- 
tic. It has generally been applied by dipping a glass rod into a solution 
formed by allowing the crystals to deliquesce, or it may be fused on the end 
of a wire. It has also been advised in 5 per cent, solution as an application 
to prevent perspiration of the feet and to harden the skin. 

The bichromate has been recommended recently in certain forms of dys- 
pepsia in doses of 5 mgs. (^ gr.). 

Bibliography. 

Priestley. Jour, of Anat. and Phys., xi., p. 285. 
Gergens. Arch. f. exp. Path. u. Pharm., vi., p. 148. 
Pander. Robert's Arb. a. d. pharm. Instit. zu Dorpat, ii., p. 1. 
Hermanni. Munch, med. Wochenschr., 1901, i., p. 536. 

Manganese. 

Traces of manganese are found in the blood and tissues of man and ani- 
mals very frequently, but this metal is not an essential constituent of the 
body, but is apparently absorbed accidentally with the food. The salts of 
manganese in large quantities cause acute irritation of the stomach and in- 
testine, like those of the other heavy metals, but no symptoms pointing to 
effects from the absorption of the metal are observed even when the adminis- 
tration is continued for a long time. 1 Manganese is absorbed from the ali- 
mentary tract, how r ever, but only in very small quantity, and it appear- to 
resemble iron closely in its course through the tissues (see page 664). Its 
general action has been elicited by the hypodermic or intravenous injection 
of double salts. In frogs manganese injected hypodermically causes a de- 
scending paralysis of the brain and spinal cord, and later weakens and 
arrests the heart, while the peripheral muscles and nerves seem unaffected. 
In mammals large injections induce epileptiform convulsions, particularly in 
the rabbit and guinea-pig. Smaller quantities, which cause a less acute intoxi- 
cation, induce in the dog, nausea and vomiting, diarrhoea, weakness, som- 
nolence, stupor and death from arrest of the respiration. The urine is often 
increased, and contains bile pigment, and, towards death, albumin and 
casts. The stomach and bowel present no congestion or ulceration in these 
cases. Manganese is found in the vomited matter and the stools, in the 
liver, kidney and intestinal wall, to a less extent in the other organs. In 
acute poisoning in mammals the blood-pressure falls, from depression and 
paralysis of the vaso-motor centre, while the heart is affected only much 
later. In subacute poisoning the darker color of the urine indicates icterus, 
but this is much more marked when small quantities are repeatedly injected 
into the subcutaneous tissues, and chronic poisoning induced. In chronic 
cases the nephritis, which is showm in acute poisoning by albuminuria, i< 
also more developed, the inflammation commencing in the secretory cells of 
the kidney but later involving the interstitial tissue, if the animal fives long 
enough. 

Manganese injected hypodermically or subcutaneously, is excreted chiefly 
by the intestinal epithelium, to a less extent by the kidney. 

Preparations. 

Mangani Dioxidum (U. S. P.), Black Oxide of Manganese . The pharma- 
copceial preparation is the crude impure mineral and need contain only 66 
per cent, of the pure dioxide (Mn< > .). 

Mangani Sulphas (U. S. P.) (MnS0 4 -j 411,0), colorless, or pale rose-colored 
crystals with a somewhat bitter, astringent taste, soluble in wain-, not in 
^lcohol. 0.1-0.5 G. (2-8 grs.). 

-1 Symptoms ascribed to chronic poisoning have recently been described by Rmbden 

as occurring in workmen in manganese. 
45 



706 THE HE A VY METALS. 

Manganese has been advised in chlorosis and especially in amenorrhea, 
in which it is believed by many to have a specific action, while others have 
found it of no value in either of these conditions. In amenorrhcea the per- 
manganate of potassium is generally prescribed instead of the dioxide or sul- 
phate, but as it is at once reduced in the stomach, the effect is the same as 
if pure dioxide was administered. 

Bibliography. 

Harnack. Arch. f. exp. Path. u. Pharm., hi., p. 58 ; xlvi., p. 372. 

Kobert. Ibid., xvi., p. 361. 

Cahn. Ibid., xviii., p. 129. 

Stockman. Brit. Med. Jour., 1893, i., p. 942. 

Embden. Deutsch. med. Woch., 1901, p. 795. 

Cadmium resembles zinc very closely in its effects. 

Nickel and Cobalt salts, administered to the frog, cause a curious dark 
color in the skin, followed by convulsive movements, which at first arise ap- 
parently from the medulla oblongata and higher centres, and resemble those 
of picrotoxin, but laier are reflex from excessive irritability of the spinal 
cord. In mammals the usual symptoms arising from the action on the in- 
testine and kidney are accompauiea by tremors and chorea-like movements, 
later by tetanus, and finally by paralysis. Strongly acid food may* form 
nickel salts when it is cooked in vessels made of this metal, but no poison- 
ing results, either because the quantity ingested is too small or because it is 
slowly absorbed from the stomach and intestine. Cobalt nitrate has been 
recommended as an antidote in prussic acid poisoning, as it forms an insoluble 
cyanide, but appears to be of little or no value ; the oxide has been applied 
externally as an astringent, antiseptic powder. 

Tin salts paralyze the central nervous system in the frog, and later the 
heart. In mammals, diarrhoea, colic, vomiting and general weakness are 
observed, along with paralysis of some parts of the central nervous system 
and stimulation of others, leading to ataxia, stiffness and irregularity of the 
movements, and occasionally convulsions. The sulphide is said to be de- 
posited in the lymph spaces of the intestines in the same way as in bismuth 
poisoning. General poisoning may be induced by the administration of the 
salts by the mouth, even when there is no corrosion of the mucous mem- 
brane. Tin is often contained in preserved foods from being dissolved off 
the vessels, and is certainly absorbed, for it has been detected in the urine 
after the use of such articles. Apparently it is not often present in sufficient 
quantities to induce poisoning, for although some cases of "tin poisoning " 
are met with in medical literature, in none of them has it been satisfactorily 
established that tin was the cause. 

Thallium salts seem to resemble those of lead in their effects, but have a 
powerful depressant action on the heart, and are said to be more poisonous. 
Richet states that the injection of thallium acetate in animals is followed by 
a general atrophy of the muscles, especially of those of the jaw and spine, 
while baldness has been ascribed to its continued use in man. 

Vanadium presents only the ordinary characteristics of metallic poison- 
ing. The different oxides vary in toxicity, the pyrovanadates being much 
the most powerful. 

Molybdenum and Tungsten resemble each other closely, and induce 
typical metallic poisoning. 

Uranium, in addition to the ordinary features of metallic intoxication, 
causes some glycosuria, the sugar often amounting to one per cent, in the 
urine. This may probably be explained by the recently discovered fact that 
this metal retards the reduction of the oxyhsemoglobin of the blood, for 
lessened oxidation in the tissues has been shown to cause some glycosuria u 
a number of instances. 

Selenium and Tellurium are classed along with sulphur in chemical sys- 



MINOR METALS. 7U7 

terns, but the salts of telluric, selenious and selenic acid induce symptoms 
resembling those of the heavy metals and arsenic in many points, and may 
be inserted in this series. In tne frog the symptoms are those of central 
nervous paralysis, and later of heart failure. In mammals vomiting, purg- 
ing, somnolence, dyspnoea, tonic and clonic convulsions have been noted, 
and the stomach is found somewhat reddened, the mucous membrane of the 
intestine swollen and dysenteric, while the kidneys seem less affected. The 
perspiration is prevented by tellurates, apparently from a paralysis of the 
terminations of the secretory nerves similar to that induced by atropine. 
An early symptom of poisoning with these bodies is a garlic odor in the 
breath, and many of the organs are found of a grayish color after death, and 
possess this odor. Hofmeister has shown that these salts are reduced to 
metallic selenium and tellurium in the body, and that afterwards methyl 
compounds (Te(CH 3 ) 2 , Se(CH 3 ) 2 ) are formed. These are volatile, and, ex- 
creted by the lungs, urine and faeces, give the disagreeable odor. The syn- 
thesis of methyl-tellurium is one of the few known cases in which a com- 
pound with methyl is formed in the animal body, and is of great biological 
importance. All the selenium and tellurium is not excreted in this form, for 
some of it appears in the urine, and probably in the faeces, in other combina- 
tions. 

Tellurates have been advised in therapeutics to prevent excessive sweat- 
ing, and certainly have this effect, but are not to be recommended, as the 
strong garlic odor of the breath persists for days or even weeks after one 
dose. 

Osmic Acid has been recommended as an injection into the nerves in 
neuralgia. It is an intensely irritant substance, and seems to induce ne- 
phritis and diarrhoea when absorbed. The greater part of the poison is, how- 
ever, deposited as a black powder at the point of injection, owing to its 
being reduced by the tissues. 

Bibliography. 
Cadmium. 

Marme. Ztschr. f. rat. Med., xxix., p. 125. 

Wheeler. Boston Med. and Surg. Journ., xcv., p. 434. 

Nickel and Cobalt. 

Stuart. Journ. of Anat. and Phys., xvii., p. 89. Arch. f. exp. Path. u. Pharm. 
xviii., p. 151. 

Bohde. Arch. f. Hygiene, ix., p. 331. 

Hdbner. Arch, internat. de Pharmacodyn. , ix., p. 339. 

Tin. 

White. Arch. f. exp. Path. u. Pharm., xiii., p. 53. 
Ungar u. Bodldnder. Ztschr. f. Hygiene, ii., p. 241. 

Thallium. 

Marme. Gottingen Nachrichten, 1867, p. 397. 

Luck. Inaug. Diss., Dorpat, 1891. 

Richet. Comptes rend, de la Soc. de Biol., 1899, p. 252. 

Vanadium. 

Priestley. Phil. Trans, of Roy. Soc, elxvi., p. 495. _ 

Gamcjee and Larmuth. Journ. of Anat. and Phys., xi., pp. 235, 251. 

Dowdeswell. Jour, of Phys., i., p. 257. 

Tungsten. 

Bernstein- Kohan. Kobert's Arbeit, a. d. pharm. Instit. zu Dorpat, v., p. 42. 

Uranium. 

Woroschihhj. Kobert's Arbeit, a. d. pharm. Instit. zu I>ori>;it. v., p. 1. 
Chittenden. Studies from the Lab. of Phys, Chem. of Sheffield Scientific School, L, 



708 THE HEA VY METALS. 

Selenium and Tellurium. 

Czapeku. Weil. Arch. f. exp. Path. u. Pharni., xxxii., p. 438. 
Hofmeister. Ibid., xxxiii., p. 198. 

Gies and Mead. Amer. Journ. of Phys., v., p. 104; Philadelphia Med. Journ., 
1901, p. 566. 



' 



PART V. 

FERMENTS, SECRETIONS AND TOXALBUMINS. 

I. DIGESTIVE FERMENTS. 

A number of digestive ferments have been introduced into thera- 
peutics for the treatment of gastric and intestinal disorders. The 
earlier members of the series were proteolytic ferments, intended to 
reinforce the pepsin of the stomach, but of recent years the amylolytic 
ferments have also been strongly advocated. 

Pepsin. 

The pharmacopceial preparations of pepsin are generally obtained 
from the pig's stomach. Their origin is not a matter of indifference, 
for it has been recently shown that pepsins obtained from different 
species of animals differ considerably in their behavior towards vari- 
ous acids. Pepsin digests only in acid solution, the best results being 
obtained in a solution of 0.2 per cent, of hydrochloric acid. (See Acids, 
page 561.) In alkaline solution it is inert, and in fact is rapidly de- 
composed, so that when pepsin and alkaline carbonates or bicarbonates 
are prescribed together, the effects are due to the alkalies only. 

Pepsin is used in therapeutics on the theory that the stomach does 
not secrete enough of the ferment in certain conditions. But it may 
be questioned whether this is true in even a small proportion of the 
cases treated with pepsin, for the gastric juice is almost always capable 
of digesting proteids if it is acid in reaction. In a number of forme 
of dyspepsia the acid secretion is insufficient, but the ferment is almost 
always present in quantity, for it digests proteids outside the body as 
soon as it is acidulated. Pepsin is indicated then, only in the rare 
cases in which the contents of the stomach acidulated with hydro- 
chloric acid fail to digest proteids. It is very often administered in 
other forms of dyspepsia, and certainly does no harm, but there is no 
question that it is entirely unnecessary in the great majority <>t' the 
cases in which it is prescribed. 

Preparations. 

Pepsinum (U. S. P., B. P.), a proteolytic fermenl obtained from tin 
dular layer of fresh stomachs from healthy pigs, and capable of digesting 
not less than 3,000 times its own weight of freshly coagulated egg albu- 
min. 1 It is a fine, white, amorphous powder ov thin scale-, free from 

lr The B. P. preparation may be obtained from the pig, sheep or calf and is required 

to digest 2,500 times its weight of hard-boiled white of c^g. 

709 



710 FERMENTS, SECRETIONS AND TOXALBUMINS. 

offensive odor and having a mildly acid or saline taste, usually followed by 
a suggestion of bitterness. It is soluble in about 100 parts of water, but is 
more soluble if the water is acidulated. 0.3-0.6 G. (5-10 grs.), in powder, 
or in solution in 0.2 per cent, hydrochloric acid. 

Pepsin is generally given during or after meals. As has been stated, it is 
very rarely indicated, as the gastric juice almost always contains sufficient 
for the ferment. 

Glycerinum Pepsini (B. P.) contains hydrochloric acid. A fluid drachm 
represents 5 grs. of pepsin. 1-2 fl. drs. 

Pepsinum Saccharatum (U. S. P.) is formed from pepsin by adding nine 
parts of sugar of milk. 

Many other preparations of pepsin are used in popular medicine, to a less 
extent by the profession. Pepsin wines, for example, are often taken as 
tonics and digestives, but the wine is probably of greater efficacy than the 
ferment. In these pepsin wines the ferment is not destroyed, however, as is 
sometimes stated, for pepsin is able to digest proteids in much stronger alco- 
holic solutions than they represent. 

Pancreatic Ferments. 

The pancreatic ferments have also been introduced into therapeutics, 
generally in the form of an extract of the gland, pancreatin. These 
ferments differ from pepsin in acting only in alkaline or neutral solu- 
tion, and besides digesting proteids, form sugar from starch and sa- 
ponify and emulsify fats. The pancreatic ferments are rendered inert 
by a comparatively short exposure to the acid gastric juice. 

The value of pancreatin is even more problematical than that of 
pepsin, for though it would no doubt be valuable where the digestive 
ferments, particularly those of the pancreas, were deficient, this has 
not been shown to occur. On the other hand, the pancreatic ferments 
are certainly destroyed in passing through the stomach. It has been 
suggested, however, that they may act in the stomach, if they are 
given before or with the food, as the acid gastric juice is only secreted 
slowly, and some time must elapse before the pancreatin is rendered 
inert. In cases in which there is a deficiency in the acid of the gas- 
tric juice, the pancreatin might conceivably act throughout the stay of 
the food in the stomach. Attempts have been made to preserve the 
pancreatin from the deleterious effects of the gastric juice by adminis- 
tering it in capsules which are dissolved only in the intestine. It is 
certainly possible that the pancreatin may be useful in certain cases, 
where the ferments of the pancreas are absent and the acid of the 
stomach so deficient as not to be destructive, but there is no reason to 
suppose that this series of accidents occurs at all frequently, and it is 
impossible to diagnose inefficiency of the pancreatic secretion. 

Preparations. 

Pancreatinum (U. S. P.), a mixture of the enzymes naturally existing in 
the pancreas of warm-blooded animals, usually obtained from the fresh pan- 
creas of the pig. It forms a yellowish, yellowish-white, or grayish, amor- 
phous powder, having a faint, not disagreeable odor and a meat-like taste, 
and is slowly soluble in water. 0.1-0.3 G. (2-5 grs.), in powder or in cap- 
sules. Keratin capsules have been proposed in order to protect the pancre- 
atin from the gastric juice. 



DIASTASE. 711 

Liquor Pancreatis (B. P.), a liquid preparation containing the digestive 
principles of the fresh pancreas of the pig. The preparation is most active 
when the animal from which it has been obtained has been fed shortly be- 
fore being killed. Two cubic centimetres of the solution ought to dij 
80 c.c. of milk. 

Benger's Liquor Pancreaticus is a solution of the pancreatic ferments 
made up with some alcohol. 

In connection with the digestive ferments may be mentioned ingluvin, an 
extract of the fowl's gizzard, which was a few years ago highly recom- 
mended as a remedy in the sickness of pregnancy, but has proved entirely 
valueless. 

Vegetable Ferments. 

Besides these animal digestive ferments, a number of vegetable proteolytic 
enzymes are known, and have eujoyed a more or less shortlived popularity. 
Prooaoly many more plant juices are able to digest proteids than are al 
present generally recognized ; thus many of the bacteria liquefy gelatin and 
albumin, and the insectivorous plants such as Drosera (sundew) and Dionea 
secrete a digestive fluid. Figs, pine apples (bromelin), the scarlet piinpernal 
(Anagallis arvensis), and many others of the higher plants have been shown 
to possess these ferments, but the best known of these is the Carica papaya, 
or pawpaw, which contains a digestive ferment known as papain, papayotin 
or papoid. This ferment acts in neutral, moderately acid, or alkaline solu- 
tion at the temperature of the body and in the cold. When swallowed it 
has no effect except its digestive action, but injected into the blood, it is 
said to paralyze the heart and central nervous system, and to cause haemor- 
rhages into the intestine ; it is very irritant in the subcutaneous tissues, 
causing pain and high fever. It has been used instead of pancreatin and 
pepsin in disorders of the digestion, and also as an anthelmintic. Diphthe- 
ritic membranes have been treated by the frequent application of papain 
solution (once an hour by some of its advocates, more frequently by others), 
and apparently with success as far as the removal of the membrane was 
concerned ; the underlying disease was not favorably influenced, however, 
and the treatment has been abandoned. Papain solution has also been in- 
jected by the hypodermic needle into tumors and abscesses, with the intention 
of digesting the new growth, or accelerating the progress of the abe 
towards the surface, but the results obtained do not encourage the further 
use of the remedy in this way. Peptones are unquestionably formed in the 
tumors when papain is injected. 

Several milk-curdling ferments have been found in plants, but none of 
them have been used in therapeutics. 

Diastase. 

Several amylolytic or sugar-forming ferments have been used more 
or less in therapeutics, the first of these being the diastase or enzym 
malt, which is known under the names of malt extract, maltzyme, 
maltine, etc. When grain is allowed to germinate, its starch i- formed 
into a soluble form (sugar) by means of a ferment known as diastase, 
and it was supposed that this diastase might aid the digestion of Btarchy 
foods in the body. When malt extract is formed at a low temperature, 
it unquestionably contains diastase and is capable of digesting starch, 
but many of the extracts on the market are quite inert, the ferment 
having been destroyed by heat. Those extracts are therefore devoid 
of digestive power, but form a pleasant, easily digested food. They 
often contain alcohol, and are then indistinguishable from beer or -tout. 



712 FERMENTS, SECRETIONS AND TOXALBUMINS. 

More recently, some other sugar-forming ferments have been brought 
forward, notably that obtained from Eurotium oryzse, a mould of the 
aspergillus family. This enzyme is known as taka-diastase from the 
name of its discoverer, Takamine, and is very much more powerful 
than any of the malt extracts, as it digests over one hundred times its 
weight of starch. Taka-diastase has been recommended in cases in 
which there is supposed to be a deficient digestion of starch. It ceases 
to act in the gastric juice as soon as the acidity exceeds 0.1 per cent., 
but may be able to digest a certain amount of starch in the mouth and 
stomach before it is destroyed. The question at once arises, however, 
whether the ordinary digestive juices are ever unable to digest the 
starch of the food. And although a new term, " amylaceous dyspep- 
sia," has been introduced to indicate this class of cases, if they should 
be found to exist, it must be admitted that no satisfactory evidence of 
their existence has been brought forward as yet. It is stated that 
more starch is found to be digested in the stomach after the administra- 
tion of diastase, but this seems to be beside the point, for it merely 
indicates that less starch reaches the intestine for the pancreatic juice 
to act upon. Until it is shown that in some cases the digestion of 
starch by the intestinal ferments is insufficiently performed, the diastase 
preparations would seem to be superfluous. According to Friedenwald, 
diastase increases the digestion of starch in the stomach chiefly in cases 
of hyperacidity, but doubt is thrown on this statement by other in- 
vestigators. 

BlBLIOGKAPHY. 

Papain. 

Hirsch. Therap. Mon., 1894, p. 609. 

Osmald. Munch, med. Woch., 1894, p. 665. 

Rossbach. Ztschr. f. klin. Med., vi., p. 527. 

Martin. Jour, of Phys., v., p. 213 ; vi., p. 336. 

Younger. Lancet, 1895, i., p. 1050. 

Chittenden, Mendel and McDermott. Amer. Journ. of Phys., i., p. 255. 

Pineapple. 

Chittenden. Jour, of Phys., xv., p. 249. 
Taka-Diastase. 

Fnedenwald. New York Med. Journ., 1897, May 29. 
Leo. Therapeut. Monatsh., 1896, p. 635. 
Strauss u. Stargardt. Ibid., 1898, p. 65. 

II. BILE. 

The bile is very seldom used in therapeutics at the present day, al- 
though it was formerly credited with great healing virtues. It has 
a bitter taste, and may have some effect like the vegetable bitters, but 
has no advantage over these, and is not likely to be used to promote 
the appetite now, although it was formerly used as a stomachic. The 
bile is found to precipitate the peptones in test-tube experiments, but 
does not appear to retard digestion in the stomach materially, judging 
from experiments carried out in a case of gastric fistula. In the intes- 
tine it is generally believed to act as an antiseptic, chiefly because the 



BILE. 713 

stools have a strong putrefactive odor in cases of retention of bile. 
Limbourg has also shown that the addition of bile to proteid solutions 
delays their decomposition, while there is some evidence that it prom 
pancreatic digestion. It has some purgative action, as is shown by the 
obstinate constipation which often occurs when it is prevented from 
reaching the intestine; according to Stadelmann, the bile acids irritate 
the mucous membrane of the large bowel and thus induce purgation. 
An obscure relation exists between the drastic purgatives and the bile 
in the intestine, several of them failing to act in its absence. 
page 98.) Another unexplained effect of the presence of bile in the 
intestine is the increased absorption of fats. Most of the bile given 
by the mouth is absorbed in the stomach and small intestine and car- 
ried to the liver, which excretes it again, while a small quantity of the 
bile acids escapes in the urine. In the liver it increases the secretion 
of both the fluid and the solids of the bile j in fact, the bile is the only 
reliable cholagogue known. The constituent which acts on the secre- 
tory liver cells seems to be the bile acids, and their increase is greater 
than can be accounted for merely by the excretion of that administered, 
so that it would seem that they exercise some specific stimulant action on 
the secretory cells. The bile pigment is also augmented when bile 
acids are absorbed, owing to the destruction of the red cells of the 
blood, as the liberated haemoglobin is carried to the liver and there 
formed into bile pigment. 

Bile given by the mouth does not cause any symptoms except those 
from the intestine and liver. When it is injected into the blood, how- 
ever, it depresses the central nervous system and the heart muscle from 
its direct action on these organs, and decomposes the red cells of the 
blood. Muscles and nerves suspended in a solution of bile salts rapidly 
lose their irritability, and some unicellular organisms are killed and 
dissolved by them. The poisonous constituent of the bile seems to be 
the salts of the bile acids, but several authors have stated t hat the 
pigment is also active. 

Frazer has recently discovered that the bile has considerable virtue 
as an antitoxin. Thus the bile of the venomous snake acts as an 
antidote to their poison, and the bile of other animals has also some 
effect in this direction. The bile acids and pigment do not seem to 
partake in the action, but the exact nature of the antidote is unknown. 
It is much more efficient when it is mixed with the poison before it- 
application, than when it is injected after the bite. Frazer adds thai 
the bile is also an antitoxin to other poisons, including those produced 
by the pathogenic microbes. Others have found that the bile of ani- 
mals dying of an infectious disease (rinderpest) possess* a some curative 
properties in other animals suffering from the same malady, this being 
explained by the excretion of the antitoxin in the bile. 

Bile has been used as a purgative, and it has been particularly 
recommended in the form of an enema. It does not Beem to be reli- 
able, however, and presents no advantages over Boaps and similar .-lib- 
stances. 



714 FERMENTS, SECRETIONS AND TOXALBUMINS. 

As a cholagogue it is without rival, but no condition is known in 
which an increase of the bile secretion is indicated, for though it has been 
proposed to expel gall-stones by raising the pressure in the gall-ducts by 
cholagogues, it is found that when the pressure is only slightly in- 
creased, the secretion is arrested. It is inconceivable that the small 
rise in pressure could force out an impacted gall-stone. 

Bile might be used to aid the absorption of fats, particularly when 
it is deficient in the bowel ; in a case of biliary fistula Joslin found that 
much less fat and nitrogenous food escaped in the stools when the 
patient was treated with bile pills, than when no treatment was adopted. 

Preparations. 

Fel Bovis (U. S. P.), ox gall, the fresh bile of the ox. 

Fel Bovis Purificatum (U. S. P.), Fel Bovinum Purificatum (B. P.), is formed 
from the fresh bile by the addition of alcohol, filtration and evaporation to 
pillular consistency. The alcohol is added to remove the mucus of the bile. 
The pigments may be removed by filtering the watery solution through airi- 
mal charcoal. 

Bile is always prescribed in the form of pills made from the purified prep- 
aration. 0.3-1 G. (5-15 grs.). 

Bibliography. 

Stadelmann. Arch. f. exp. Path. u. Pharm., xxxvii., p. 352. Ztschr. f. Biolog., 
xxxiv., p. 1. 

Rywosch. Arb. a. d. pharm. Instit. zu Dorpat, ii., p. 102 ; vii., p. 157. 

Limbourg. Ztschr. f. phys. Chem., xiii., p. 196. 

Pjaff and Balch. Journ. of Exp. Med., ii., p. 49. 

Fraser. Brit. Med. Journ., 1897, ii., pp. 125 and 595 ; 1898, ii., p. 627. 

Joslin. Journ. of Exp. Med., v., p. 513. 

III. INTERNAL SECRETIONS. 

Until very recently the only animal secretions recognized in thera- 
peutics were the digestive ferments, the bile, and a few rarely used sub- 
stances, such as musk. But within the last few years it has been 
shown that certain glands supply the blood constantly with substances 
which are necessary to the economy, and a deficiency in which leads to 
the gravest symptoms. The subject of internal secretion is still in its 
infancy, but therapeutics has already been enriched with at least one 
addition of unquestioned value, and may profit still more by the fur- 
ther exploration of this field. The chief object of "organotherapeu- 
tics," or the treatment of disease with extracts of the glands of the 
body (animal extracts), has been to supply a deficiency of the normal 
secretion. At the same time, it is possible that a wider field of useful- 
ness may be developed, for there is no reason why these animal extracts 
should not have a true pharmacological action, as well as the vegetable 
extracts. Advance in organotherapeutics is not, however, to be ex- 
pected from the indiscriminate use of the gland extracts in every sort 
of disease, such as is too popular at present. Such progress as has 
been made hitherto in this field has been due to careful observation 
and experiment, and not to haphazard use of the hypodermic syringe. 



THYROID EXTRACT. 715 

Thyroid Gland. 

The treatment of certain diseases by the administration of thyroid 
gland and its extracts is one of the most satisfactory examples of ra- 
tional therapeutic progress, and the steps which led to its adoption may 
therefore be briefly mentioned. In 1882-3, Kocher and Reverdin 
published observations made on patients whose thyroids had been totally 
extirpated, and who had subsequently presented a series of symptoms 
to which these observers gave the name of cachexia thyreopriva. They 
pointed out that this condition resembled in many of its features 
myxoedema, a disease discovered by Gull some years before and asso- 
ciated with atrophy of the thyroid gland. These observation- were 
confirmed by a number of authors, who removed the thyroid- from 
animals, and found a cachexia appear in them. The next advance 
was the discovery that these symptoms in animals could be removed, 
or at any rate ameliorated, by grafting pieces of thyroid in the peritoneal 
cavity or subcutaneous tissue. Horsley suggested that myxoedema 
should be treated in the same way, and Murray soon afterwards intro- 
duced the treatment of this disease by the subcutaneous injection of 
thyroid juice. Even in his first case, the results were eminently satis- 
factory, but it was soon found that the same results could be obtained 
by administration by the stomach, and a large number of cases have 
now been recorded in which very favorable results, or even the complete 
disappearance of the symptoms has followed this medication. These 
include not only myxoedematous patients, but also cases in which the 
thyroid was removed by surgical operation, or where its disease gave 
rise to symptoms. That the favorable results are due to the treat- 
ment is proved conclusively by the return of the symptoms when it is 
abandoned. 

The effect of the thyroid extract could be explained only by the 
presence of some unknown principle, for the preparation of course con- 
tained no living cells. In the last few years, numerous researches 
have been carried out with the object of isolating this principle. 1 It 
is found in the colloid contents of the gland follicles in the form of 
a globulin, thyreoglobulin, which may be extracted from the colloid 
and gives the ordinary proteid reactions, but is characterized by con- 
taining about 1.5 per cent, of iodine ; Baumann's detection of this ele- 
ment in the thyroid gland was the first intimation that it existed in the 
tissues of the higher animals and man. Thyreoglobulin is not com- 
pletely saturated with iodine, for it forms a higher combination with it 
in the test-tube, but then loses its specific action on the animal organ- 
ism. When it is subjected to artificial digestion, it forma albumoses 
and an insoluble non-proteid substance known as Todothyrin, 1 winch 
contains practically all the iodine of the gland. A similar result is 
obtained by acting on thyroid gland, colloid, or thyreoglobulin with 

1 No attempt is made to follow the chronological order of these reaearc] 
2 Iodothyrin was at first named llvji-owdin, but this was liable to be confused With 
thyreoidin, a term used to indicate the simple extract of the gland. 



716 FERMENTS, SECRETIONS AND TOKALBUMINS. 

acids. Iodothyrin is readily dissolved in dilute alkaline solutions and 
may be reprecipitated by acids. It contains more iodine than thyreo- 
globulin of course, but the exact percentage is still a disputed point, 
for while Baumann originally stated that it contained about ten per 
cent., others have found it as low as four per cent., and Oswald's analy- 
sis gives no less than fourteen per cent, for iodothyrin obtained by the 
action of acids, and about five per cent, for that formed by digestion. 
Much remains to be done, therefore, before the composition of iodo- 
thyrin can be definitely settled, but it is certain that it is not a proteid 
and that it is rich in iodine and nitrogen, while sulphur is present in 
smaller amount, and phosphorus is not contained in the molecule. 

The amount of iodothyrin in the gland varies a good deal in differ- 
ent animals, and in different individuals of the same species. It was at 
first supposed that in the goitre districts the percentage of iodothyrin 
in the gland was lower than in healthy areas, and that in cases of 
goitre the percentage was smaller than in normal individuals, but this 
seems to be incorrect, no relation existing apparently between the 
amount of iodine in the thyroid and the presence of endemic goitre. 
As a general rule it is found that the iodine and iodothyrin of the 
glands vary directly with the amount of colloid material. In children 
less iodine is found in the gland than in adults, and after middle age 
it lessens again. Meat diet diminishes the amount of iodine, either 
because it makes greater demands on the supply, or because too little 
iodine is ingested in the food. Vegetable foods, especially those con- 
taining much iodine, such as beetroot and probably the marine algae, 
increase the iodine of the thyroid gland. Iodine given medicinally 
also augments it, and not only iodine itself, but various combinations, 
such as iodoform and iodides. It is not yet determined whether 
actually more iodothyrin is formed under these conditions, or whether 
that already present contains more iodine. 

A number of other constituents have been isolated from the thyroid 
gland in a condition of greater or less purity, some of them proteids 
and others crystalline non-proteid bodies ; but none of them possess 
the specific action of the gland extract and in fact none of them have 
been shown to induce any effect at all except those which it may be 
supposed contained iodothyrin. On the other hand, thyreoglobulin 
and iodothyrin induce the same effects as the extract both in myxe- 
dema and goitre in man and in excision of the thyroid in animals. This 
has been disputed until recently owing to a misapprehension of the ef- 
fects of thyroidectomy in animals, which was supposed to be inevitably 
fatal unless thyroid extract was administered. As a matter of fact, 
dogs (on which these experiments have been performed generally) may 
react in three different ways to excision of the thyroid and subse- 
quent thyroid feeding. In a small number the operation is not fol- 
lowed by any serious symptoms and the animal recovers completely, or 
at any rate survives for many months. In the great majority thyroid- 
ectomy is followed by tremors, convulsions, paralysis and death in the 
course of a few weeks, but some of these can be kept alive and free 



THYROID EXTRACT. 717 

from spasms by feeding them thyroid extract or iodothyrin. A third 
class is formed of those animals which suffer from spasms and even- 
tually succumb to them even when supplied with abundant thyroid ex- 
tract. The exact proportion of these three classes, those which live 

without extract, those which are saved by it, and those which perish 
in spite of it, appears to vary at the hands of different investigators 
and perhaps in different regions, and this has given rise to erroneous 
views as to the value of the different preparations. But the balance of 
evidence is in favor of the view that iodothyrin represents the whole 
therapeutic virtues of thyroid extract, although it is possible that the 
gland may have other functions than its secretion. Iodothyrin and 
thyroid extracts are thus used to replace the secretion of the thyroid 
gland, when it is deficient from any cause. The function of the thy- 
roid gland is still very obscure, however, although it is now certain 
that it is of great importance in the metabolism, as is clearly shown by 
the disastrous results of its removal or atrophy. The results of the 
injection of the thyroid extract have also thrown much light on the 
working of this mysterious organ. 

Action. — The thyroid extracts and iodothyrin seem to be devoid of 
effect in many normal animals and patients, unless when given in enor- 
mous quantities. In others they cause some unpleasant symptoms. 
Which occur more especially in myxcedema and goitre. These symp- 
toms are partly subjective and indefinite, such as headache, wandering 
pains, or general weakness, while others are evidently due to circula- 
tory changes, and consist of a feeling of fullness and congestion of the 
head, palpitation of the heart, and acceleration, sometimes weakness, 
of the pulse. Tremors in the arms and legs point to changes in the 
central nervous system, while loss of appetite and diarrhoea indicate 
that the alimentary canal is not exempt from its influence. Perspira- 
tion is often complained of, especially in myxoedema, and a rise of 
temperature also occurs not infrequently. 

In normal animals iodothyrin injected intravenously in large quan- 
tities generally accelerates the heart and lowers the blood-pressure 
somewhat, and even when given by the mouth repeatedly for several 
days, it causes some acceleration. This acceleration of the heart has 
been attributed by some investigators to stimulation of the accelerator 
centre, by others to direct action on the heart ; L it does not seem to 
due to any changes in the inhibitory apparatus. 

Loss of flesh and thirst have been observed, even when the appetite 
is good and sufficient food and water are supplied. The urine i- uni- 
formly increased in amount. Lanz observed some dyspnoea and occa- 
sional diarrhoea, sometimes with blood in the stools, along with a ourious 
stiffness in the hind legs. Most of his dogs treated by hypodermic in- 
jections died after a longer or shorter time, but he i- inclined to look 
upon this as due to putrefactive products in the preparations which he 

^yon has recently stated that iodothyrin increases the irritability of the inhibitor} 
terminations in the heart, but this is opposed to the well-established fact that the h 
is accelerated by thyroid preparations. 



718 FERMENTS, SECRETIONS AND TOXALBUMINS. 

used. Hellin has asserted, however, that thyroid extract which lias 
not undergone putrefaction, causes gastro-enteritis, nephritis, cloudy 
swelling of the cells of the liver and spleen, and paresis of the 
hind legs. Cunningham, on the other hand, asserts that fresh 
thyroid is not poisonous to normal dogs, but this is again disputed by 
Georgiewsky. 

Some of the symptoms induced in man by an overdose of thyroid 
resemble those seen in exophthalmic goitre or Graves' (Basedow's) 
disease, and exophthalmos has been observed in monkeys to which 
large amounts of thyroid were given. 

As may be gathered from the above, great discrepancies occur in the 
accounts of the effects of thyroid on normal animals. The accelera- 
tion of the heart and the fall in weight seem to be the most common 
results, and it is certainly possible that the other symptoms described 
are due to the injection of albumoses and other putrefactive products. 

The effects of thyroid extract on the Metabolism have been repeat- 
edly examined, with very uniform results. One of the most striking 
features in many individuals is the rapid loss of weight, which often 
amounts to several pounds per week. Another is the increase in the 
amount of nitrogen in the urine, which occurs both in goitre and 
myxoedema, and very often in apparently normal persons. More ni- 
trogen is excreted in the urine frequently than is taken in the food, 
that is to say, the iodothyrin leads to the destruction of the proteids of 
the tissues. If more nitrogenous food be given, however, this may be 
arrested, and in fact if large quantities of meat be taken, less nitrogen 
may be excreted than is taken in the food, so that although the patient 
is losing in weight, he may be actually increasing in nitrogenous tis- 
sue. If, on the other hand, a patient has been put in nitrogenous 
equilibrium, and then under iodothyrin begins to excrete more nitro- 
gen than he ingests, this excessive tissue waste is not stayed by in- 
creased carbohydrates and fats ; that is, the carbohydrates and fats 
cannot replace nitrogenous food to the same extent as in normal individ- 
uals. Iodothyrin has thus a specific effect in increasing the waste of 
the proteids of the body. But this increased waste of the proteids 
only accounts for about one-sixth of the loss of weight, the other five- 
sixths being evidently due to the more rapid oxidation of fats and the 
removal of fluid from the body. 1 The more rapid oxidation is further 
evidenced by the increased amount of oxygen absorbed and of carbonic 
acid exhaled by the lungs in cases of myxoedema and sometimes in 
obesity and goitre treated with the extract. The removal of fluid from 
the body, perhaps the most potent factor in reducing the weight in 
these cases, is shown by diuresis, which occurs in myxoedema especially, 

1 Schondorff states that in nitrogenous equilibrium the oxidation of the fats is in- 
creased before the proteids of the body are attacked, but when the fat destruction has 
reached a certain point, the proteid waste is also increased. The early augmentation of 
the nitrogen of the urine does not indicate an acceleration of the proteid metabolism, 
but is due to the removal of urea and other products, which have been formed in the 
tissues before the administration of the remedy, but which are now excreted through 
the increased activity of the kidneys. 



THYROID EXTRACT. 719 

but also in obesity. This diuresis has been ascribed to some specific 
action on the kidney, or to the changes in the circulation, but may per- 
haps be due to the increased excretion of urea and other urinary sub- 
stances. That the kidney is acted on in some cases is shown by the 
occasional appearance of albumin in the urine of patients treated with 
thyroid, but it is still undetermined whether this is due to the iodothyrin 
or to some other body, perhaps of putrefactive origin. 

The phosphates excreted are increased in the same ratio as the nitro- 
gen, and the increase is obviously due to the same cause, augmented 
proteid waste. 

In some cases sugar has been found in the urine after thyroid treat- 
ment, and in a considerable percentage of persons it seems to cause a 
tendency to glycosuria, as is shown by the appearance of sugar in the 
urine after the ingestion of large quantities of sugar, which would 
normally be oxidized in the tissues. The uric acid excretion does not 
seem to be materially affected by thyroid treatment. 

After iodothyrin has been administered, iodine is found in the urine 
in the form of iodides, so that the iodothyrin is evidently decomposed, 
at any rate in part, in the body. The rest of the iodine is taken up 
by the thyroid gland, and it would appear probable that it enters into 
it in the form of iodothyrin, and that no preliminary decomposition 
occurs here. 

In regard to their reaction to thyroid medication, individuals vary consid- 
erably, for many are scarcely affected by it in any way, and this is particu- 
larly true of children, while others lose weight rapidly, and under larger 
doses show symptoms of poisoning (thyroidism). These seem to be more 
easily elicited in goitre and myxoedema than in ordinary cases. On the 
other hand, in Grave's disease the symptoms are generally aggravated by 
thyroid treatment, although a few cases are recorded in which it gave relief. 
Many authorities therefore believe that Grave's disease is due to the over- 
production of iodothyrin, but this has not yet been proved, although there 
is considerable support for the theory. 

The fact that "thyroidism" occurs more frequently in myxedematous 
than in normal persons seems difficult of explanation, but it has been >uu r - 
gested that the symptoms are due not to the iodothyrin itself, but to the 
products of its action. It may be supposed that in myxoedema a large 
amount of some substance accumulates in the tissues, because the iodothyrin 
is not present in sufficient quantity to decompose it, and that when the thy- 
roid treatment is commenced, the body is flooded with the products of de- 
composition and these give rise to symptoms. In normal persons, on the 
other hand, there is no such accumulation, and iodothyrin therefore induces 
no symptoms until it is given in such quantity as to induce intoxication it- 
self. In Grave's disease the iodothyrin would, of course, tend to aggravate 
the symptoms, if these are due to its excessive production. Until moi 
learned of the action of iodothyrin and of the cause of Grave's disease, how- 
ever, these explanations are mere hypotheses, and they need not be entered 
upon further here. 

Iodine, as has been stated, increases the iodothyrin ol' the gland, and this 
perhaps explains the beneficial effects formerly seen in goitre from the applica- 
tion of iodine internally and locally. When iodine was efficient in t 
cases, and any considerable diminution of the gland occurred, it vu often 
accompanied by symptoms exactly resembling those produced l>\ la: 



720 



FERMENTS, SECRETIONS AND TOXALBUMINS. 



of iodothyrin. Those symptoms were caused by small quantities in some 
patients, while much larger doses had no such effects in others — a fact which 
gave rise to some discussion and several erroneous theories. Sometimes the 
acute symptoms passed into a cachexia of very long standing. The quan- 
tity of iodine required to act in goitre is much greater than the iodine of the 
iodothyrin necessary, and this shows that the latter acts not merely as an 



Fig. 51. 



Fig. 52. 





A case of sporadic cretinism. Fig. 51, before treatment, age 23 months, height 28 inches, cir- 
cumference of the abdomen 19 inches. Fig. 52 after treatment with thyroid extract for 5% months, 
height 30 inches, circumference of abdomen 15 inches. (Osler. ) 

iodine compound, but as the specific substance of the gland. Various iodine 
compounds, such as iodalbumin and iodospongin (the iodine compound of the 
sponge) have been shown to be practically inert in goitre. 1 



PREPARATIONS. 

Thykoideum Siccum (B. P.), a powder prepared from the fresh and 
healthy thyroid gland of the sheep. It forms a light, dull-brown powder 
with a faint, meat like odor and taste, free from any odor of putrescence. 
About 16 grs. represent an entire gland. Dose, 3-10 grs. 

1 In this account of the action of the thyroid extract and its constituents, the gen- 
erally accepted view has been given, namely, that the thyroid gland secretes a substance 
into the blood which is necessary to the normal life of the organism. It must be added 
that Blum advocates the theory that the thyroid gland retains its colloid substance in 
its interior and employs it to destroy a poisonous proteid formed in the course of metab- 
olism. The grounds for this view seem quite inadequate, however, and the reader may 
be referred to the numerous papers of Blum on the subject. 



THYROID EXTRACT. 721 

Liquor Thyroidei (B. P.), a liquid prepared from the fresh and healthy 
thyroid gland of the sheep, and containing some phenol. A pinkish, turbid 
fluid, entirely free from any odor of putrescence. It ought to be freshly pre- 
pared. 6 c.c. (100 mins.) represent an entire thyroid gland (5-15 mins.). 

Thyroid medication may be carried out in a number of different 
The old method of ordering the raw or toasted gland to be taken daily may 
now be said to be rendered obsolete by more elegant preparations, Buch as 
dried thyroid or thyroid extract in powder form or in pills or tablets, or the 
liquor. These ought not to be prescribed in large quantities as the 
liable to undergo putrefaction unless when carefully kept ; iodothyrin tablets 
have also been introduced, each containing 0.001 G. (..V gr.) or more of iodine. 
The dose should be small at first (e. g., \ gr. of the dried gland or 2-3 mins. 
of the liquor every evening for the first week of treatment) and should be 
gradually increased, until improvement sets in or unpleasant symptoms 



Therapeutic Uses. — Iodothyrin is not a dangerous remedy, unless In 
certain cases. In myxcedema, however, it should be used with care, 
especially if the heart is seriously affected, as the cardiac muscle may 
be unable to meet the requirements of the accelerated rhythm; several 
serious cases and one or two fatalities have already been recorded in 
these conditions. 

Iodothyrin is useful as a substitute for the normal gland secretion 
in cases where the latter is wanting or deficient, as in myxcedema, 
cachexia thyreopriva, goitre and sporadic cretinism. In all of these 
the medication has to be continued for a long time, perhaps through- 
out life, as otherwise the patient relapses into his former condition. 
The decrease in weight occurring in thyroid medication suggested its 
use in obesity, and it has been followed by some loss of weight in a 
certain number of cases, especially when accompanied by proper die- 
tetic treatment. In many instances it has had little or no effect, how- 
ever, and the initial encouraging action is seldom maintained when the 
treatment is continued, the daily loss of weight gradually becoming 
smaller until it ceases altogether. The amount of fat actually de- 
stroyed seems to be trifling, Magnus-Levy estimating that about one 
pound disappears in ten days, which is much less than can he go! rid 
of by judicious exercise and an appropriate dietary. Besides the 
continued use of thyroid in these cases is not altogether devoid of 
danger. 

In some skin diseases, especially in psoriasis, it has been of benefit, though 
not by any means invariably, and in syphilis of old standing some impn 
ment has been seen. This is probably due to the iodine contained, and do1 
to the specific gland secretion. At the same time the peculiar combination 
in which the iodine is present may perhaps be more easily made use of by 
the economy than the ordinary inorganic preparations. 

The improvement seen in the brain symptoms in myxoedema and cretin- 
ism suggested its use in other mental diseases, hut the action in the former 
is due to its substitution for the normal secretion, and little or no effecl has 
followed in ordinary cases of mental disease. 

In Graves' disease it seems generally to he injurious. A curioua relation 
appears to exist between thyroid and the thymus gland, lor the administra- 
tion of the latter is often attended by some relief in this disease. 
46 



722 FERMENTS, SELRETIOISS AM) T0XALBUMIN8. 

i)JJ)J JOGE APHY. 

Baumann u. Boos. Ztschr. f. physiologische Chemie, xxi., xxii. 

Rous. Ibid., xxi., xxii., xxv., pp. 1 and 242; xxviii., p. 40. 

Baumann u. Ooldmann. Munch, med. Woch., 1896, p. 1153. 

Ewald. Die Erkrankungen der Schilddriise — M yxa-dem and Cretinismus, Wien, 
1896. 

M'obius. Die Basedow' sche Krankheit, Wien, 1896. These two are contained in 
Nothnagel's Specielle Pathologie und Therapie, Bd. xxii. 

Hutchison. Brit. Med. Journ., 1896, i., p. 722; 1897, i., p. 194. Journ. of Phys., 
xx., p. 474; xxiii., p. 178. 

Oswald, Zts. f. phys. Chern., xxiii., p. 265; xxvii., p. 14 ; xxxii., p. 121. 

Schondorff. Pfliiger's Arch., lxiii., p. 423 ; lxvii., p. 395. 

David. Zts. f. Heilkunde, xvii., p. 439. 

JSchiff. Wien. klin. Woch., 1897, p. 277. 

Bettmann. Berl. klin. Woch., 1897, p. 518. 

Treupel. Munch, med. Woch., 1896, p. 117. 

Bleibtreu u. Wendelstadt. Deutsch. med. Woch. , 1895, p. 346. 

Zinn. Berl. klin. Woch., 1897, p. 577. 

Blum. Pfliiger's Arch., lxxvii., p. 70. 

Volt. Ztschr. f. Biol., xxxv., p. 116. 

Cunningham. Journ. of Exp. Med., iii., p. 147. 

Magnus-Levy. Ztschr. f. klin. Med., xxxiii., p. 269. 

JDonath. Yirchow's Arch., cxliv., Supplem. , p. 253. 

Notkin. Ibid., p. 224. 

Hellin. Arch. f. exp. Path. u. Pharm., xl., p. 121. 

Howell, Chittenden, Adami, Putnam, Kinnicutt and Osier. Transactions of the Con- 
gress vof American Physicians and Surgeons, iv., pp. 70-206. 

Berkeley. Johns Hopkins Hospital Bulletin, 1897, p. 137. 

Cyon. Pfliiger's Arch., lxx., pp. 126, 511, 643. 

Ver Eecke. Arch, de Pharmacodynam., iv., p. 81. 

Tambach. Ztschr. f. Biol., xxxvi., p. 549. 

Anderson u. Bergmann. Skand. Arch. f. Physiol., viii., p. 326. 

Georgiewski. Ztschr. f. klin. Med., xxxiii., p. 153. 

Uaskovec. Arch, internat. de Pharmacodyn., viii., p. 167. 

Edmunds. Proc. Roy. Soc, lxv., p. 368. 

Murray. Practitioner, 1901, April. 

Other Internal Secretions. 

Extract of the Suprarenal or Adrenal Glands. See p. 463. 

The extracts of the Pituitary Body or rather of its posterior lobe or in- 
fundibular body, cause some changes in the circulation, owing to their con- 
taining two substances which have been termed the pressor and depressor 
bodies. The arterial tension is increased by the extract or by the pressor 
body, but the rise is smaller than that induced by suprarenal extract, 
although it is maintained longer. The heart is slowed, partly through in- 
hibitory action, partly from direct action on the muscle. The depressor 
body causes a transient fall in the blood pressure. The hypodermic injection 
of large quantities of the extract is followed by paralysis in mammals. 
Schiff found that extract of the hypophysis caused a marked increase in the 
excretion of phosphates in a case of acromegaly and in a healthy old man, 
while it had no effect on a younger individual ; he attributes this to the ex- 
tract tending to increase the destruction of the bone tissue. Acromegaly is 
generally regarded as being connected in some way with disease of the hy- 
pophysis, but the extract does not seem to modify the disorder in most cases, 
although improvement has been stated to occur sometimes. 

The Thymus Gland has been found to contain minute quantities of an 
iodine compound, which may be identical with that of the thyroid. Svehla 
found that the injection of an extract into the veins caused considerable ac- 
celeration of the pulse with some depression of the blood-pressure. The 
acceleration was found to be due to direct action on the heart, the fall of the 
blood-pressure to paralysis of the vaso-constrictors. Very large quantities 



INTERNAL SECRETIONS. 723 

caused restlessness, collapse and death. Thymus extract has been to 

in exophthalmic goitre, and is said to be of some value in a certain Dumber 

of cases, but does not benefit most patients. 

The excision of the Pancreas in animals is followed by the appeanj 
sugar in large quantity in the urine, and in many oases of diabetes in the 
human subject the pancreas is found diseased, so that this gland Be* 
secrete some substance which is required by the tissues to enable them to 
maintain the normal amount of sugar in the blood. Extract of pancn 
therefore been administered in diabetes, but as yet without satisfactory re- 
sults in the ordinary form of the disease. 

Bone Marrow extract and Spleen extract have been given in pernicious 
anaemia in order to increase the number of the red cells, and many other 
extracts of organs have been proposed, often on the most extraordinary 
grounds. It was not to be expected that these extracts of brain, heart, liver, 
kidney, prostate and lung would prove of benefit in the diseases of these 
organs, and experience has shown that they may without exception be rele- 
gated to the realms of quackery. 

One extract deserves mention on account of the attention it has attracted, 
and the influence it has had on the theory of organotherapeutics — the ex- 
tract of the Testicles. The use of testicular extract was fust recommended 
by Brown-Sequard in 1889, as having a general tonic effect. He was led to 
this conclusion by the consideration that the sexual power is diminished in 
advanced life and made the bold step from this, that one of the causes of the 
woes of old age is the diminution of the internal secretion of the i 
this elixir of youth might, however, be obtained by extracting the organs in 
various ways. It is surprising how widely this theory has been accepted, 
and with what zeal all sorts of preparations of the testicles and ovaries, in- 
cluding the unaltered human semen, have been used in therapeutics, and. it 
must be adied in justice to the observers, in experiments upon themselves. 
While there is no question that the removal of these organs exercises an im- 
portant influence on a number of organs and tissues, there are no sufficient 
grounds for believing that the testicular extract has any effect whatsoever 
except through hypnotic suggestion. Two investigators have recently at- 
tempted to demonstrate the increase in the muscular strength by means of 
the ergograph, but the results obtained by means of this instrument in other 
investig itions have proved so deceptive, that little weight is to he laid on 
their results. Loewy and Richter state that extract of testicle increases the 
oxilation in the tissues of male castrated animals, but not in normal male 
anim .lis or in castrated females ; extract of ovary (pophorin) has a similar 
effect on the castrated female. 

Instead of the extract of testicle, spermine, an alkaloid found in the testicle 
chiefly, but also in a number of other organs, has been proposed by Poehl. 
According to this author, it is an important factor in the oxidation of the 
tissues, and a number of symptoms of disease are due to its being precipi- 
tated in the form of the phosphate and thus rendered inactive, this being 
especially liable to occur whenever the alkalinity of tin' blood is reduced in 
any way. Poehl's spermine has therefore been advised in a large number 
of diseases, and in fact is considered by some almost a panacea Hi- state- 
ments are not founded on any satisfactory experimental or clinical obs 
tions, and have met with little credence from experienced physicians. Sper- 
mine was at one time supposed to be identical with piperazine hut this Im- 
proved to be erroneous. 

BlBLIOGllAPIIY. 
On Pituitary Gland. 

Schafer and Oliver. Journ. ofPhys., xviii., p. 277. 
Howell. Journ. of Exp. Med., iii., p. 245. 
Schiff. Wien. klin. Woch., 1897, p. 277. 
Malretet Bosc. Arch, dc Phys. (5\ viii.. p. 600. 



724 FERMENTS, SEC 'EETIONS < I ND TOXA LB l r MIJNS. 

Cleghorn. Araer. Journ. of Phys., ii., p. 282. 
Schafer and Vincent. Jour, of Physiol., xxv., p. 87. 

On Thymus Gland. 

Svehla. Arch. f. Exp. Path. u. Pharm., xliii., p. 321. 
Kinnicutt. Cong, of Amer. Phys. and Surg., iv., p. 157. 

On Testicular Extract (experimental). 

Zoth. Pfluger's Arch., lxii., p. 335 ; lxix., p. 38G. 

Pregl. Ibid., lxii., p. 379. 

Loewy u. Richter. Arch. f. [Anat. u.] Phys., 1899, Suppl., p. 174. 

Dixon. Journ. of Physiol., xxvi., p. 244. 

On Spermine. 

Bulk. Therap. Monatsch., 1896, p. 22. 
Spitzer. Berl. klin. Woch., 1895, p. 695. 
Poehl. Ztschr. f. klin. Med., xxvi., p. 135. 

IV. TOXALBUMINS. 

A series of bodies, whose existence has only been recognized in the last 
few years, but whose importance in medicine is ever increasing, is that of 
the poisonous proteids or toxalbumins. The idea that a proteid can pro- 
duce dangerous or even fatal symptoms, or act in any way except as a food, 
dates only from 1884, but many of the animal poisons are now believed to be 
of proteid nature, and the toxins formed by the micro-organisms of disease 
are almost certainly of the same general class. The description of most 
of these must be relegated to the text-books on bacteriology and pathology, 
but some toxalbumins which are associated with drugs in daily use deserve 
short mention. 

Ricin is an intensely poisonous globulin found in the seeds of Ricinus 
communis along with castor oil, which does not itself contain this principle, 
however. Ricin is poisonous in doses of about -£■$ milligram (r^W gr.) per 
kilogram body weight when it is injected into the blood, and is somewhat 
less poisonous when applied subcutaueously, but seldom causes any symp- 
toms when swallowed, as it is apparently destroyed for the most part by the 
digestive ferments. It is thus among the most powerful of the vegetable 
poisons when it is injected directly into the blood. Death often occurs only 
several days after the injection in animals, and in the interval no symptoms 
make their appearance except some loss of appetite, and towards the end, 
diarrhoea and vomiting. Post-mortem, the bowel is found inflamed and 
congested and contains ecchymoses ; blood is found in the serous cavities, and 
extravasations may occur in various other organs, although not so uniformly 
as in the bowel. Among the most obvious lesions are the innumerable 
ecchymoses in the great omentum and the swelling of the abdominal 
lymph-glands, which generally contain numerous small haemorrhages. 
Microscopical examination reveals small foci of necrosed tissue in the 
liver, spleen, intestine, stomach and other organs. Ricin seems to be ex- 
creted by the intestinal epithelium, which may explain the violence of its 
action here, although it acts as a poison in many other tissues. It is a 
powerful irritant, inducing inflammation and suppuration when it is injected 
subcutaneously, or is applied to the conjunctiva. On the other hand it has 
little or no irritant action on the mouth and throat, and is digested and 
rendered harmless in the stomach. The mucous membrane of the nose is 
irritated by the inhalation of the powder in many persons. This toxoglobu- 
lin has a very characteristic action on the blood. When a drop of a dilute 
solution is added to a test-tube of defibrinated blood, the corpuscles soon 
fall to the bottom, leaving the clear serum above, and the blood does not filter 
through paper any longer, the corpuscles all remaining on the filter, the serum 
passing through colorless. This is due to the agglutination of the red cells, 



TOXALBUMINS. T->: 



<_'•> 



which are formed into masses and thus fail to pass through the pores of the 
filter. Fibrin does not seem to be formed in the process, as was at one time 
supposed, but the nature of the cementing substance is unknown Stillmark 
supposed that ricin formed these masses of red cells in the blood vessels and 
that the symptoms were due to the emboli resulting, but this is certainly in- 
correct, for the blood of immune animals reacts in the same way, vet these 
are not poisoned by many times the usual fatal dose of ricin. 

Ehrlich found that animals rapidly acquired immunity to the action of 
ricin, if they received for some time small non-toxic doses. From this dis- 
covery has arisen the whole of serum-therapeutics, which plays such an im- 
portant role in medicine at the present time. By gradually Increasing the 
daily amount of ricin, rabbits have attained an immunity of 5,000 thai is 
they are not affected by 5,000 times as much ricin as would have killed 
them had no preliminary treatment been instituted. This immunity is en- 
tirely different from the tolerance acquired for morphine and other drugs 
for the latter is due to the cells of the body becoming accustomed to being 
constantly bathed in a fluid containing the alkaloid. The same tolerance 
is acquired by various marine animals, which would be killed if suddenly 
changed to fresh water, but which are gradually acclimatized, if the change is 
made more gradually by adding increasing proportions of fresh water to 
the sea water of the aquarium. The immunity acquired for ricin and other 
toxalbumins is, on the contrary, due to the formation in the body of a sub- 
stance which antagonizes the original poison, and which is known as an 
antitoxin, in this case antiricin. This antagonistic substance circulates in 
the blood, and can be withdrawn from the immune animal and injected into 
a second, which then acquires a certain degree of immunity, although less 
than that of the first. In tolerance, then, the tissues become indifferent to 
the poison; in immunity they form an antitoxin. Antiricin is antagonistic 
only to ricin ; it does not protect an animal from any other toxalbumin. 

Ricin and antiricin are not used in therapeutics, out ricin has repeatedly 
given rise to poisoning, from the beans being taken as a substitute for the 
oil. Cattle have also been poisoned by being fed on the refuse of castor oil 
beans after the oil had been expressed. 

Another vegetable toxalbumin which resembles ricin very closely in its 
effects is Abrin, which is obtained from the seeds of Abrus precatorius orje- 
quirity, the familiar scarlet and black beans, which are often formed into 
necklaces. Abrin contains two poisons, a globulin and an albumose, of 
which the former is the more powerful. It induces the same symptoms 
as ricin, but is less poisonous, and immunity can be acquired in the same 
way. Animals which are immune to ricin are not more resistant to the ac- 
tion of abrin than others, because the two poisons form different antitoxins, 
Abrin or jequirity has been used as an irritant to the eye in cases of granu- 
lar lids and of corneal opacities. It causes an acute inflammation which 
improves the condition in some cases, but it must be regarded as an exceed- 
ingly dangerous remedy, as the inflammation is entirely beyond the control 
of the surgeons. In animals the eye is often completely destroyed by the 
application of abrin, while in other experiments enough of the drug is ab- 
sorbed to cause fatal poisoning. 

Crotin is another toxalbumin, which is found in the Croton Tiglium, but 
which does not pass into croton oil. It is less poisonous than ricin and ab- 
rin, but resembles them in most other points, except that it d<>e^ not cause 
agglutination of the blood cells of certain animals, while ricin and abrin 
have this effect in all kinds of blood hitherto examined. Many other plants 
contain toxalbumins, but none of them have aroused so much in! 
those mentioned above. 

.Many animals produce proteid poisons, such as the Bnakes, the poison 
lizard, Heloderma suspectum (Gila monster), several amphibia and fish, and 
the scorpions and spiders (tarantula). On the other hand, several insect 



726 FERMENTS, SECRETIONS AND TOXALBUMINS. 

poisons which resemble these poisons in their irritant action and in some 
other points, have been shown not to be proteids. An antitoxin for snake 
poison has been introduced recently under the name of antivenin, and is 
found in the bile of poisonous snakes and in smaller quantities in that of 
other animals. These animal poisons and the bacterial poisons, however, 
can be treated of with advantage only in special text-books. 

Bibliography of Ricin, Abrin and Crotin. 

Stillmark. Arb. a. d. pharm. Instit. zu Dorpat, iii., p. 59. 

Martin. Proc. Roy. Soc, xlii. 3 p. 331 ; xlvi., p. 94. 

Hellin. Inaug. Diss., Dorpat, 1891. 

Ehrlich. Deutsch. med. Woch. , 1891, Nos. 32 and 44. 

F/exner. Journ. of Exp. Med., ii., p. 197. 

Elfstrand. Robert's Gorbersdorfer Veroffentlichungen, i., p. 1. 

Mixller. Arch. f. exp. Path. u. Pharm., xlii. , p. 302. 

Jacoby. Ibid., xlvi., p. 28 ; Beitriige z. Chem. Phys. u. Path., i., p. 51. 

V. COD-LIVER OIL. 

Cod-liver oil has been long used by the fishermen of the North Sea 
as a remedy in children's diseases, and was introduced into medicine 
in the beginning of last century, but became generally used only in 
the last fifty years. 

It is obtained from the liver of the cod-fish (Gadus morrhua), and 
probably from other members of the genus. Formerly the livers were 
left to decompose, and the oil set free by the breaking up of the cells 
was collected. It had a most disagreeable odor and taste, however, 
and many patients could not be induced to take it, while those who 
were courageous enough to swallow it, often suffered from eructation 
and diarrhoea afterwards. This method was therefore soon replaced 
by the " steam-process," in which the oil is melted out of the fresh 
livers, yielding an oil of much lighter color, and with much less dis- 
agreeable smell and taste. Quite recently a new process has been intro- 
duced, by which the oil is extracted by steam, without being exposed 
to the air, and it is stated that oil thus obtained is less disagreeable 
than any other. 

The cod-liver oils used in therapeutics differ considerably in appear- 
ance and in composition, the older preparations being brownish in 
color, and having a strong fishy odor and a somewhat acrid, disagree- 
able taste, while the oil prepared by the more recent process is pale 
yellow in color, and has much less odor and a bland taste. 

Cod-liver oil probably contains the ordinary constituents of an ani- 
mal fat, olein, stearin and palmitin, but the relative proportion in 
which these are present is unknown. Some free fatty acid is gener- 
ally found in it, the darker preparations containing some 4—7 per cent, 
the pale yellow oil less than one per cent, as a general rule. 

Iodine and bromine are present in traces, apparently very much smaller 
in amount than is generally believed. The usual statement is that 0.03- 
0.04 per cent, of iodine and 0.003-0.005 of bromine exists in the oil, but some 
oils have been found to contain only about one-hundredth of this amount of 
iodine. 

Phosphorus is found in traces in some oils, in an organic combination, 



COD-LIVER OIL. 7 27 

not in the free state. A small percentage of cholesterin ig often, not invari- 
ably present, and bile acids and pigments have hen said to occur, hut this 
seems incorrect. A number of bases have been found in cod-liver oil by 
Gautier, especially in the darker colored varieties, while the pale yellow 
oil contains little or none. These bases or alkaloids (leuoomaineej an- 
Butylamine (C 4 H U N), Amylamine (C 5 H I3 N), MexykmilU (( il \ Dihy- 
drolutidine (C 7 H n N) and two new non-volatile ones, AsseHne a.nd Morrhuine. 
They were found combined with morrhuic, formic, butyric and other acid-. 
Trimethylamine has also been said to occur in it. 

Heyderdahl has recently stated that cod-liver oil contains no ohii, or 
stearin and only some four per cent, of palmitin, the hulk of the oil h« in- 
made up of therapin, jecolein and other similar bodies ; these are all glycer- 
ides of unsaturated acids of the oleic acid series except therapin, wSich i- 
the glyceride of an acid with several unsaturated carbons. All of these 
acids change to oxyacids in the air and then cause eructation when swall 
He attributes the benefits arising from cod-liver oil treatment to these riy- 
cerides, which, he considers, are readily assimilated by the tissues and 
which are not present in any other food. But it seems unlikely that this 
fat should be so entirely different from all other animal fats, and Heyder- 
dahl' s statements certainly require confirmation before they can be accepted. 

Cod-liver oil has no very distinct action when taken in ordinary 
doses, while in large quantities it has a tendency to cause eructation, 
nausea and diarrhoea. Taken repeatedly, it increases the weight and 
strength, and improves the general condition. The same effects are 
obtained in healthy persons by the use of good food and fats, hut deli- 
cate patients who are unable to digest ordinary animal fats, are able 
to take cod-liver oil. Its effects are obviously those of an easily as- 
similable food, and it is not a drug in the ordinary sense of the term, 
and has therefore no place in pharmacology properly speaking, but 
should be classed along with other foods. It is always treated of as 
a drug, however, because it has often been supposed to have some 
cific effect quite apart from ordinary foods. It is generally believed 
to differ from ordinary fats in being more readily assimilable, but the 
explanation of this fact is by no means agreed upon, for though it is 
often said to be more rapidly absorbed from the intotine, there is lit- 
tle reliable evidence that such is the case. A few experiments have 
been carried out, but by no means enough to establish the truth of the 
statement satisfactorily, and the chief argument brought forward in 
its support is that cod-liver oil forms an emulsion in the test-tube 
more rapidly than other oils. It is undoubtedly well borne by the 
stomach, but it has not been often compared with other oils in regard 
to this point, and it is still impossible to state that other oils adminis- 
tered with the same care as cod-liver oil are not equally successful 
remedies. 

Buchheim explained that cod-liver oil formed an emnlsioB rapidly 
on account of the free acid it contained, and this ! 
put forward as accounting for its effects in therapeutics. \- far as 
regards the old dark-colored oils, this explanation may hold gnocf, bat 
the pale oil now used in therapeutics often contain- less free acid than 
ordinary olive oil. Some enthusiastic supporters <>!" Buchheim's th< ory 
have, therefore, asserted that the pale «>il does n,»t give the same results 



728 FERMENTS, SECRETIONS AND T0XALBUMIN8. 

as the older, less pure, acid preparations, but this is not the general 
opinion of the medical profession. 

The older explanations started from the view that cod-liver oil is a drug, 
that the oil itself is only a means to administer certain active principles 
contained in it. Thus iodine and phosphorus were in turn supposed to be 
the essential constituents, but have both been shown to be present in too 
small quantities to be of any effect. More recently cholesterin has been 
suggested as the curative agent, but it is present in smaller quantities in 
cod-liver oil than in many other foods. 

Lastly the bases have been credited with lending cod-liver oil all its vir- 
tues. But the pale oil contains only traces of these, and again the state- 
ment has been made that the brown oil is superior. An attempt has been 
made to support this theory by examining the urine of persons under treat- 
ment with the bases separated from the oil. The urine has been found in- 
creased in amount, the urea augmented, the less oxidized forms of nitrogen 
diminished, but these experiments are of no value, because apparently no 
measures were taken to keep the amount of food ingested constant. 

Several substitutes for cod-liver oil have been proposed, such as Lipanin 
(v. Mering), which is formed from olive oil by the addition of 6 per cent, of 
oleic acid, and which was suggested by the theory that cod- liver oil owes its 
rapid absorption to the presence of free acid. A mixture of cacao butter 
and oleic acid has also been introduced, as well as oil of sesame and olive 
oil. On the theory that the bases were the indispensable part of the oil, 
Morrhuol, a crude mixture of bases, acids and pigment, has been introduced 
into therapeutics and used to some extent, but it has not proved a substitute 
for the oil in practice. Lipanin has been used only to a limited extent, and 
has not been able to supplant cod-liver oil, although, like oil of sesame and 
olive oil, it has the advantage of being much less disagreeable in smell and 
taste. This may perhaps be due to the conservatism of the medical profes- 
sion, rather than to the special merits of cod-liver oil. 

On the whole, cod-liver oil has not been shown to have any action 
apart from that of an easily digested food, and its superiority to some 
other fats and oils has not been satisfactorily established. 

Preparation. 

Oleum Morrhtj^: (U. S. P., B. P.), cod-liver oil, Oleum Jecoris Aselli, 
a fixed oil obtained from the fresh livers of Gadus Morrhua and of other 
species of Gadus, — a pale yellow, thin, oily liquid, with a peculiar, slightly 
fishy, but not rancid odor, and a bland slightly fishy taste. 4-16 c.c. (1-4 
fl. drs.). 

Therapeutic Uses. — Cod-liver oil is used in chronic wasting diseases, 
such as tuberculosis, scrofula, rickets and some forms of syphilis. It 
is especially beneficial in the earlier stages of pulmonary phthisis, but 
has no specific virtues here or elsewhere apart from those of an easily 
digested fat. In all forms of malnutrition and delicacy in children, it 
is largely used, and undoubtedly causes a considerable increase in 
weight, but care must be taken that it does not disturb the digestion, 
especially if the darker oils are used. In some persons pure cod-liver 
oil always induces nausea, but a much larger number refuse to take 
the brown oil. In most cases the light-colored oil is taken readily, 
especially if the dose be small at first (a teaspoonful). When there is 
dyspepsia or a tendency to diarrhoea, cod-liver oil should be given 



PHLORIDZIN. 729 

with caution, and it is generally prescribed only in cold weather. 
as it is found that patients have a distaste for it in summer. When 
fever or acute disease is present, cod-liver oil is generally found of 
little value, perhaps on account of the disturbed condition of the 
digestion. Cod-liver oil should not be forced on patients; when it 
continues to induce nausea and eructation after a fair trial, it should 
be abandoned. 

Innumerable means have been proposed to conceal the odor and 
taste, but it is generally conceded that when possible the pure oil \s 
better given alone. When patients cannot be indued to- take it in 
this way, some volatile oil, ether, or brandy may be added to it; 
saccharine has also been used to sweeten it. Creosote is sometimes 
mixed with cod-liver oil in cases of phthisis, or an emulsion La formed 
containing cod-liver oil, some flavoring substance, iron, hypophos- 
phites or calcium. Extract of malt and cod-liver oil form a common 
mixture, and are the basis of many patented emulsions. 

In general, the pale oil is preferred, but it must be added that some 
physicians persist in the use of the darker forms, which contain more 
bases and more free acid, but have a much more disagreeable taste and 
smell, and are more liable to disturb the digestion. Of the substitutes 
for cod-liver oil, lipanin has little taste and is generally taken readily. 
It may be given shaken up in milk, or formed into an emulsion. 

BlBLIOGKAPHY. 

Naumann. Arch, der Heilkunde, 1865, p. 536. 

Buchheim. Arch. f. exp. Path. u. Pharra., iii., p. 118. 

V. Mering. Therap. Monatsh., 1888, pp. 49 and 233. 

Salkowski. Ibid., 1888, p. 230. 

Hauser. Ztschr. f. klin. Med., xiv., p. 543 ; xx., p. 239. 

Lowenthal Arch. f. Anat. u. Phys., 1897, p. 258. 

Mersereau. New York Med. Journ., 1899, ii., p. 11. 

Sternberg. Ztschr. f. klin. Med., xxii., p. 295. 

Bouillot. Compt. Kend. de l'Acad. des Scien., ex v., p. 754. 

Gautier et Mourgues. Les Alcaloides de Huile des Foies de Morue, Paris, 1S90. 

Heyerdahl. F. Pekel Mailer's Cod-liver Oil and Chemistry, London, 1895, p. 88. 

VI. PHLORIDZIN. 1 

Phloridzin is not used in therapeutics, but has attracted sonic attention 
from its effects in animals, and may therefore be mentioned shortly. It is 
a glucoside (C 21 H 24 O 10 + 2H 2 0) found in the rootbark of the apple, ]< 
cherry and plum tree. When given in large quantities by the mouth it 
sometimes causes some diarrhoea in animals, but apart from this ite only 
effect is glycosuria, which also follows its Injection subcutaneous^ or intra- 
venously. The urine is found to contain 5-15 per cent, or even more of 
sugar, sometimes along with acetone and oxybutyric acid, bo that the in 
ication seems at first sight to resemble diabetes mellitua in man very closely. 
Phloridzin induces the same results in man, and the glycosuria is not accom- 
panied by any other symptoms generally. It differs from true diabetes, 
however, in the fact that the sugar of the blood is not increased in amount* 
The glycosuria is not due to any change in the general metabolism of the 
body, therefore, but to some alteration oi' the renal epithelium, by which 

1 Phloridzin is not in any way related to the other drugs of this part, and hlfl only 
been inserted here because no suitable position could be found else* 



730 FERMENTS, SECRETIONS AND TOXALBUMINS. 

the blood sugar escapes into the urine instead of being retained in the body 
and used as a source of energy. This has been definitely proven by Zuntz, 
who showed that when phloridzin was injected into one renal artery, the 
urine secreted by the corresponding kidney contained sugar, while that from 
the other remained normal for some time. As the available sugar is drained 
off in the urine, the tissues rapidly manufacture more and pour it into the 
blood. As long as sufficient food is given, the loss of sugar does not seem to 
entail any increase in the destruction of the proteid tissues, but when phlo- 
ridzin is given to starving dogs, the waste of sugar has to be made up from 
the tissues, and the nitrogen of the urine accordingly rises in amount, while 
at the same time the liver cells become infiltrated with fat globules. The 
statement that the sugar of the milk is increased by phloridzin has proved 
to be incorrect. 

Glycosuria may be maintained for an indefinite time if the administration 
of phloridzin be continued, and animals recover rapidly when the treatment 
is stopped. The glucoside is probably excreted in the urine unchanged, 
although this has not been quite satisfactorily demonstrated as yet. Phlo- 
ridzin may be decomposed into a sugar, phlorose, and phloretin, which also 
induces glycosuria. 

Syzygium Jambolanum, a tree growing in South America and in the East 
Indies, is said to contain some unknown substance which has a specific action 
in diabetes. Several clinical observers have observed improvement in some 
cases, but others have seen no result whatever follow, and as a general rule, 
no sufficient estimation of the sugar of the urine was made in the cases in 
which the treatment was believed to be successful. Some experiments on 
animals seem to indicate that it modifies the sugar formation in the tissues, 
but cannot be accepted uutil they are confirmed by further research. 

Bibliography of Phloridzin. 

V. Mering. Zts. f. klin. Med., xiv., p. 405 ; xvi., p. 431. 
Rosenfeld. Ibid., xxviii., p. 256. 

Zuntz. Arch. f. Anat. u. Phys. (Phys. Abth.), 1895, p. 570. 
Coolen. Arch, de Pharmacodynam., i., p. 267 ; ii., p. 255. 

Kulz, Wright, Moritz, Prausnitz, Cremer, Ritter, Lusk. Zts. f. Biol., xxvii., xxviii., 
xxix., xxxvi. 

Reilly, Nolan and Lusk. Am. Jour, of Phys., i., p. 395. 
Levene. Jour, of Exp. Med., ii., p. 107. 
Pappenhevm. Arch. f. Verdauungskrank., iii., p. 421. 
HUdebrandt. Virchow's Arch., cxxxi., p. 26. 



PART VI. 

MENSTRUA AND MECHANICAL REMEDIES. 

Oleum Theobromatis (U. S. P., B. P.), cacao-butter, a fixed oil 
from the seeds of Theobroma cacao, forms a yellowish-white solid having a 
faint, agreeable odor and a bland, chocolate taste. It melts a little below 
the temperature of the body. Cacao-butter is used almost exclusively 
form suppositories, in which astringents and other remedies are incorporated. 
When these are introduced into the rectum, they melt and the active prin- 
ciple is liberated. 

Keratin (not official) is a substance obtained from horns, hoofs, nails, etc. 
which is insoluble in the gastric juices, but is dissolved by the alkaline pan- 
creatic secretion. It is used to coat pills which it is desired to protect from 
disintegration in the stomach. 

Kaolinum (B. P.), or porcelain clay, is used in the formation of pills < son- 
taining easily reduced bodies, such as silver nitrate or potassium permanj 
nate. Mixed with the ordinary vegetable excipients, such as confection of 
roses, or extract of liquorice or gentian, these salts would be reduced at 
once. Kaolin is an aluminium silicate and forms a soft whitish powder in- 
soluble in water or dilute acids. 

Sapo (U. S. P.), Sapo Duras (B. P.), hard soap, white Castile soap, is pre- 
pared from soda and olive oil. 

Sapo Mollis (U. S. P., B. P.), soft soap, sapo viridis, a soap made from 
potash and olive oil. 

Sapo Animalis (B. P.), curd soap, soap made with sodium hydroxide and 
a purified animal fat consisting chiefly of stearin ; it contains about 30 per 
cent, of water. 

These soaps are used in therapeutics as ingredients of liniment- and plan- 
ters. Water containing soap is often thrown into the rectum as an enema. 
and in infants a soapstick inserted into the anus generally provokes evacua- 
tion of the bowels in a few minutes. 

Soaps impregnated with antiseptics, such as perchloride of mercury, car- 
bolic acid, tar, or iodine, are often used to disinfect the hands. 

The chief preparations in which soap is used in the pharmacopoeias are : 

Emplastrum Saponis (U. S. P., B. P.), soap plaster. 

Linimentum Saponis (U. S. P., B. P.), soap liniment. 

Linimentum Saponis Mollis (U. S. P., B. P.). 

The liniments consist of alcohol with soap in suspension, perfumed with 
volatile oils, and are mildly irritant to the skin. They are used targel] 
bases for other liniments. 

The use of the oils, fats and glycerin as vehicles for the application of 
remedies to the skin has been mentioned already (page 49). They may also 
be usei to dissolve remedies which are insoluble in water, but which are to 
be given by the mouth, such as phosphorus (in oil). 

Wax (cera alba, cera flava) is used chiefly to increase the consistency of 
ointments. A special series of preparations somewhat stiller than the oint- 
ments are the cerates of the U. B. l\ 

Plasters are sticky adhesive substances which are chiefly used to give me- 
chanical support, but which are often impregnated with active remedies in 
order to elicit their local action on the skin. The basis of many of the | 
ters is lead plaster, which is obtained by the action of lead oxide on olive 
oil and consists for the most part of lead oleate. 

731 



732 MENSTRUA AND MECHANICAL REMEDIES. 

Emplastrum Flumbi (IT. S. P., B. P.), lead or diachylon plaster. 

Emplastrum Resinse (IT. S. P., B. P.), adhesive plaster. 

Emplastrum Saponis (IT. S. P., B. P.), soap plaster. 

Emplastrum Opii (IT. S. P., B. P.), opium plaster. 

Emplastrum Belladonnse (IT. 8. P., B. P.), belladonna plaster. 

Emplastrum Picis Burgundies (IT. S. P.), Emplastrum Picis (B. P.), Bur- 
gundy pitch plaster. 

Emplastrum Capsici (IT. S. P.). 

Emplastrum Amies (IT. S. P.). 

Emplastrum Picis Canlharidatum (IT. S. P.), warming plaster. 

Emplastrum Calefaciens (B. P.), warming plaster. 

Emplastrum Cantharidis (B. P.). 

Emplastrum Hydrargyri (IT. S. P., B. P.), mercury plaster. 

Emplastrum Ammoniaci cum Hydrargyro (IT. S. P., B. P.). 

Emplastrum Plumbi Iodidi (B. P.). 

Emplastrum Ferri(\J. S. P.). 

Emplastrum Menthol (B. P.). 

Emplastrum Ichthyocollve (IT. S. P.), isinglass plaster or court plaster. 

Court plaster is formed from isinglass, the dried swimming bladder of sev- 
eral species of sturgeon, which is dissolved in water, alcohol and glycerin 
and painted on taffeta. Isinglass differs from lead plaster and its deriva- 
tives in being transparent, so that if it be spread on a flesh-colored cloth, it 
disfigures the hands and face less than the others. 

Lead plaster, resin plaster and isinglass plaster are used only to cover and 
protect cuts and abrasions, and to keep the edges of wounds in apposition. 
The adhesive plaster and isinglass plaster are superior to lead plaster, as they 
stick more firmly. It is perhaps unnecessary to add that plasters are always 
applied spread on cloth. Opium and belladonna plasters are believed to 
lessen pain locally as well as to give support, but this is perhaps imaginary. 
Belladonna plaster is said to lessen the secretion of perspiration and of milk. 
The pitch, arnica, menthol and capsicum plasters have some irritant action 
and this is of course more marked in the case of the warming plaster and 
cantharides plaster. Some mercury is absorbed when the mercury plasters 
are applied to the skin, but this method of administration allows of even less 
accurate dosage than inunction, and is seldom used. Iron plaster is devoid 
of any properties apart from those shared with the others. 

Another series resembling the plasters in their sphere of usefulness is 
formed by the Collodia. Their basis is pyroxylin, or soluble gun-cotton, 
which is formed from cotton by the action of sulphuric and nitric acids, and 
which consists of a mixture of nitrates of cellulose. Collodion is formed by 
dissolving pyroxylin in a mixture of alcohol and ether. When these evapo- 
rate, there remains a fine layer of pyroxylin, which protects the surface to 
which it is applied and gums the edges of slight cuts together. This collodion 
is rendered less brittle by the addition of Canada turpentine and castor oil in 
small proportions, and is then known as flexible collodion. A blistering 
collodion is formed by the addition of powdered cantharides to the flexible 
preparation. Another preparation contains tannic acid. 

Pyroxylinum (IT. S. P., B. P.), soluble gun cotton, colloxylin. 

Collodium (IT. S. P., B. P.), collodion. 

Collodium Flexile (IT. S. P., B. P.), flexible collodion. 

Collodium Cantharidatum (IT. S. P.), Collodium Vesicans (B. P.), blistering 
collodion. 

Collodium Stypticum contains 20 per cent, of tannic acid. 

Instead of collodion, india-rubber, Caoutchouc (B. P.), Elastica (U. S. P.), 
may be dissolved in chloroform and applied in the same way. 

Calcii Sulphas Exsiccatus (IT. S. P.), Dried Gypsum, and Liquor Sodii SUi- 
catis (IT. S. P.), solution of waterglass, are used to impregnate bandages, 
which then become hard and immovable. The waterglass bandage is lighter 
than the plaster of Paris (gypsum) one, but has not been so widely used. 



CLASSIFICATION OF DRUGS ACCORDING TO 
THEIR THERAPEUTIC USES. 



I. Drugs applied for their local action 
to the skin, wounds or visible 
mucous membranes. 

Corrosives or caustics. 
Potash, 544 
Mercury nitrate, 654 
Potassium and sodium carbon- 
ate, 544 
Silver nitrate, 691 
Zinc chloride, 688 
Nitric acid and other acids, 559 
Chromic acid, 704 
Burnt alum, 700 
Bromine, 586 
Arsenic, 607 
Lead nitrate, 674 
Trichloracetic acid, 568 
Ammoniated mercury and 
other mercury preparations, 
654 

(Soda, 544) 

(Sodium e thy late, 549) 

(Lime, 569) 

(Carbolic acid, 398) 

Disinfectants and antiseptics. 
Hydrogen peroxide, 591 
Permanganate of Potassium, 

591 
Chlorine, 586 ^| not np . 

Sulphurous anhy- I plied to 

dride, 566 Hiving 

Formaldehyde, 428 J objecLS 
Carbolic acid, 398 
Corrosive sublimate and other 

mercury salts, 654 
Silver nitrate, 691 
Zinc chloride, 688 
Boracic acid, 582 
Iodoform, Iodol, 521 
Cresol, 404 
Tar, 410 

Salicylic acid, 413 
(Benzoic acid, 423) 
{ Camphor, 430) 
(Sulphites, 533) 
(Sulphocarbolates, 422) 
(Volatile oils (thymol, eucal- 

yptol, etc.) ) 

Astringents. 

Tannic acid scries, 111 
Iron preparations, e. g., sul- 
phate, 659 



II 



Bismuth preparations, 896 

Lead acetate, (>74 
Zinc sulphate and oxide 
Copper sulphate, 684 
Alum, 700 

Styptics. 

Soluble astringents (see above) 
Iron perchloride, 659 

Silver nitrate. »i ( .»l 
Burnt alum, 700 

To contract vessels and reduce / 
rhaye and /wetting. 
Cocaine, 302 

Suprarenal extract (adrenalin). 
463 

Emollients or protective*. 
Emollients, 49 
Plasters and Collodia, 732 
Dusting powders — starch, tal- 
cum, chalk. .">:! 
and many insoluble metal- 
lic powders which may 
also be slightly astrin- 
gent. 

Local anodynes an'/ analgesics for pain 

and itch in;/. 
Bicarbonate of potassium, 5 » 1 
Cocaine, eucaine, orthoform, 

etc., 302 
Carbolic acid. 398 
Chloretone, 187 
(Prussic acid. 239) 
( Atropine. 27H) 
(Aconite. 332) 
(Vera trine, 38) 

Local anaesthetics. 

Cold by evaporation ol ether. 

etc., 182 
( locaine and eucaine, • 

Drugs used for affections of the 
alimentary tract. 

BiOTJTB \ni> THBO \ I 
Demuicet ■ 

Chlorates 

ammonium chloride. 
Cubebs, 
To l ess en laJtraftoa, atropine, 
279 



788 



734 



THERAPEUTIC CLASSIFICATION. 



Flavoring substances. 
Sugars, 54 

Volatile oil series, 66 
Acids (citric), 559 
Syrups of Tolu, ginger, 
etc. 
Stomach. Digestives. 

Pepsin, papain, etc., 709 
Hydrochloric acid, 565 

Emetics. 

Common salt, 490 

Mustard, 89 

Warm water 

Apomorphine, 235 

Ipecacuanha, 343 

Tartar emetic, 625 

Copper sulphate, 688 

Zinc sulphate, 691 
(Alum, 700) 
(Ammonium carbonate, 
554) 
To lessen irritation and vomiting. 

Opium, 207 

Chloral, 187 

Lime water, 569 

Bismuth, 696 

Cerium oxalate, 700 

Cold (ice) 

Cocaine, 302 

Carbonic acid water, 584 

Demulcents, 45 

(Prussic acid, 239) 
To lessen acidity, antacids. 

Potassium and sodium car- 
bonate and bicarbonates. 
544 

Magnesia and magnesium 
carbonate, 544 

Lime water and chalk, 569 

Lithium carbonate, 544 
To increase secretion^ bitters. 

Simple bitters, 56 

Nux vomica and strych- 
nine, 196 

Cinchona and quinine, 357 

(Hydrastis, 230) 

(Salicin, 413) 
Carminatives. 

Volatile oil carminatives, 
61 

Alcoholic preparations 

Carbonic acid Avaters, 584 

Carbonates and bicarbon- 
ates, 544 

Bitters (see above) 

Camphor, 430 

Charcoal, 581 

Ammonium carbonate, 544 

(Peppers, 72) 
Intestine. To promote digestion. 

(Pancreatin, 710) 

(Diastase, 711) 



To promote evacuation — purgatives. 

Vegetable purgatives, 95 

Saline cathartics, 535 

Mercurial purgatives — cal- 
omel and metallic prep- 
arations. 638 

Sulphur, 577 

Enemata 

Glycerin suppositories, 51 

(Atropine) 

To lessen movement and relax spasm. 
Opium and morphine, 207 
Tannic acid series, 111 
Lime water, 569 
Lead acetate, 674 
Bismuth, 696 
Atropine (to relax spasm), 

279 
(Alum, 700) 

To destroy parasites — anthelmintics. 
Male fern, ll8 
Pomegranate, 121 
Cusso, etc., 120 
Santonin, 122 
Calomel, 638 
Salol, 413 

(Some volatile oils) 
(Chloroform, 182) 
(Thymol, naphtol, 405) 
(Quassia enema, 56) 

Disinfectants and antiseptics. 

(Vegetable and Saline 

Purgatives) 
Mercurial Purges — Calo- 
mel, 638 
Naphtol, 408 
Salol, 413 

III. Drugs used for their effects on 
the circulation. 
Heart. To strengthen contraction. 
Digitalis group, 440 

To accelerate puke. 
atropine, 279 
(Camphor, 430) 
(Caffeine, 245) 

To slow the pulse. 

Digitalis group, 440 
Aconite, 332 
Veratrine, 338 
Strychnine, 196 

Vessels. To contract calibre and raise 
blood-pressure. 
Digitalis, 440 
Strychnine, 196 
Caffeine, 245 
Camphor, 430 
Ergot, 476 



THERAPEUTIC CLASSIFICATION. 






To relax vessels and lower blood- 
pressure. 
Nitrite series, 468 

To arrest internal haemorrhage \ 

(styptics). 
Ergot, 476 
Hydrastine and hyrasti- 

nine, 230 
Opium and morphine (to 

allay restlessness) 

To remove jluid (dropsy, anasarca). 
Digitalis series, 440 
Diuretics (see kidney be- 
low) 
Saline cathartics. 535 
Diaphoretics (see skin, be- 
low) 
(\ egetable cathartics, 95) 
(Salicylic acid, 413) 

IV. Drugs used for their effects on 
the genito-urinary system. 

To increase the jiow of urine (diuretics). 

Caffeine and theobromine, 245 

Digitalis and squills, 4-10 

(Turpentine, uva ursi, sco- 
parius) 

Nitrates, 531 

Acetates, bob 

Citrates, iodides of the alka- 
lies, 510 

Carbonates, 544 

Mercury — calomel and blue 
pill, 638 

To render the urine less acid. 

Alkali carbonates and bicarbon- 
ates. 544 
acetates, bob 
citrates, 556 

To render the urine antiseptic. 
Copaiba series, 75 
Salol and salicylates, 413 
Sodium sulphocarbolate, 422 
Borax, 582 
Urotropin, 553 

Local antiseptics, astringents, 
anodynes, caustics, etc.. are 
used in the urethra and blad- 
der. 

To promote contraction of the uterus 
(ecbolics). 
Ergot, 476 
Quinine. 357 
(Pilocarpine. 315) 
(Cottonroot-bark. 476) 
(Hydrastis. 230) 

To promote menstruation (emmena- 
gogues). 
Iron. 659 

Vegetable purgatives— a Iocs. 95 
( Myrrh | 



V. Drugs used for their effects on the 

respiratory system. 
To stimulate // 
Ai ropine 
< affeine, 24."> 

( amphor. 430 

Strychnine, 196 
(Alcohol ?) 

To redact- the irritability of ths centre in 
cough. 
Opium, morphine :>nd codeine, 

207 
i Hei 

Chloral Berjes, I 87 
Bromides of the alkali.--. 504 

To increase and liquify ■ 
secretion. 
Ipecacuanha. 34."! 
Tartar emetic. 033 
Squills, 440 
Senega. 350 
Ammonium carbonate. 
Iodides of the alkalies, 510 
(Lobelia, 278) 

To lessen the secretion of the bronc) 
Benzoic acid, benzoin, 
balsam, 423 

Ammonium chloride. 500 
Cubebs. 75 

To relax bronchial $jKi.<m (?) in 
Belladonna and atropim 
Lobelia. 
Nitrite series, 
Iodides. 510 

(Charts potassii nitratU 
(Aspidosperma, 354 

VI. Drugs used for their effects on the 

Central Nervous System. 
Stimulants. 

(«) 



The spina! 
Strychnine, 

(6) The brain and mxiulla 
lonyata. 
Atropine (COC&UM 
( lamphor, 

Cailiine. 



h- 



Depn 






J 

' m. nitrous 

( toium and morphine 
Alcohol, I'M 
Chloral gi 
Bron 

1 1 \ " 

( 'annabis indi< i 






736 



Til ERA PE UTIC CLASSIFICA TION. 



To relieve pain — analgesics or an- 
odynes. 

Opium, 207 

Cannabis, 233 

Antipyrine series, 373 

(Alcohol, 131) 

(Chloral, 187) 

(Arsenic, iodides, quinine, 
nitrites are sometimes 
of value in headache) 

VII. Drugs used to reduce fever tem- 

perature. 
Antipyrine and acetanilide 

group, 373 
Quinine, 357 
Aconite, 332 
Salicylic acid group, 413 
Diaphoretics (see below) 
(Resorcin, guaiacol, 406) 

VIII. Drugs used for their effects on 
the liver. 

To increase the secretion of bile — chola- 
gogues. 
Ox gall, 712 
(Salicylic acid, 413) 

IX. Drugs used for their effects on the 

blood. 

To increase the haemoglobin. 

Iron, 059 

Arsenic, 007 
To increase the alkalinity. 

Alkali carbonate group, 544 

Acetates and citrates, 554 

X. Drugs used for specified diseases. 

In Malaria. 

Quinine, 357 

Arsenic, 607 
In Syphilis. 

Mercury, 638 

Iodides, 510 
Rheumatic Fever. 

Salicylates, Salol, 413 
Myzcedema and some other thyroid 



Thyroid extract, 715 
Gout. 

(Colchicum, 347) 

XI. Drugs used for their effects on the 
skin. 

■ Corrosives or caustics, 733 
Emollients and protectives, 733 
Local anodynes and anaesthetics, 733 
Irritants. 

Turpentine oil group, 86 

Mustard, 89 

Cantharides, 90 

Croton oil, 99 

Tartar emetic, 633 



Camphor, 430 
Menthol, 430 
Iodine, 517 
Ammonia, 555 
(Aconite, 332) 
(Veratrine, 338) 

Disinfectant or irritant ointments in 
parasitic skin diseases. 

Mercury ointment, 638 

Sulphur ointment, 577 

Tar, 410 

Ichthyol, 412 

Benzoin, storax and Peru bal- 
sam, 423 

Xaphtalin and naphtol, 408 

Resorcin, 400 

Thymol, 405 

Pyrogallol, 407 

Chrysarobin, 104 

( 'aniphor, 430 

Boracic acid, 582 

lodol and other organic iodine 
compounds, 521 

Organic bismuth preparations, 
700 

Alum preparations, 702 

Arsenic, iodide of potassium, 
etc.. may be used internally 
in skin diseases 
Drugs administered internally to increase 
the secretion of perspiration {dia- 
phoretics or sudorifics). 

Ipecacuanha, 343 

and other nauseating ex- 
pectorants (antimony) 

Ipecacuanha and opium (Dov- 
er's powder), 343 

Camphor, 430 

Pilocarpine, 315 
Drugs administered internally to lessen 
the secretion of perspiration. 

Atropine and belladonna, 279 

Agaricin, 301 

Camphoric acid, 430 
Drugs applied locally and internally to 
arrest the secretion of milk. 

Atropine 

XII. Drugs used locally for their 
effects on the eye. 

Astringents, 733 
Disinfectants, 733 
Caustics, 733 

Anodynes and anaesthetics, 733 
Drugs dilating the pupil and relaxing the 
accommodation — mydriatics. 

Atropine and hoinatropine, 279 

Cocaine, 302 

(Gelseminine, 265) 
Drugs contracting the pupil and the 
ciliary muscle — myotics. 

Physostigmine or Eserine, 324 

Pilocarpine, 315 

(Muscarine, 315) 



INDEX 



The preparations are not mentioned in the index unless when they are ;:><-t with in the 
text apart from the chief constituent, e.^., Tinctura Digitalis will be found un-i- r Digitalis; 
but Lead plaster is indexed, because it occurs apart from lead. For metallic salts, 
text under the metal, e. g. t for Mercury perchloride, see Mercury. 



ABIES excelsa, 86 
Abrin, 84, 725 
Abrus precatorius, 725 
Absinthe, 65, 68 

Absorption from the alimentary tract, 
32 

lungs, 32 

rectum, 34 

skin, 33, 49 

subcutaneous tissues, 33 

wounds, 34 
Acacia, 47 

catechu, 114 
A. C. E. mixture, 180 
Aceta, 40 
Acetal, 129 
Acetaldehyde, 429 
Acetanilide, 373 
Acetate of ammonium, 557 
Acetates, 554 
Acetic acid, 567 

ether, 71, 181 
Acetone-chloroform, 129 
Acetoperacid, 592 
Acetophenone, 128 
Acetylene, 128 
Acid, acetic, 567 

agaric, 301 

angelic, 338 

arabinic, 47 

arsenic, 608 

arsenious, 608 

benzoic, 391,423 

boracic, 582 

boric, 582 

bromacetic, 129 

butyric, 129 

cacodylic, 608 

caffeotannic, 357 (note) 

cambogic, 105 

camphoric, 302, 430, 433, 435 

carbolic, 390, 398 

carbonic, 584 

cathartinic, 101 

cetraric, 59 

chloracetic. 129 

chromic. 594, 704 

chrysophanic, 101, 104, 124 

cinnamic, 391, 424, 42.'> 

47 



Acid, citric, 569 

cresotinic, 391,422 
crotonoleic, 99 
digallic, 114 
ergotinic, 476, 482 
filicic, 118 
fiavaspidic, 118 
formic, 568 
gallic, 111, 114 
gallotannic, 114 
gymnemic, 306 (note) 
hippuric, 423 
hydriodic, 514 
hydrohromic, 508 
hydrochloric, 565 
hydrocyanic, 68, 239 
hydrofluoric, 525. 567 
hydrosulphuric, 579 
jalapinic, 105 
lactic, 568 
lupulinic, 58 
meconic, 207 
muriatic, 565 
nitric, 565 

nitrohydrochloric, 565 
ophelic, 59 
opianic, 230 
osmic, 707 
oxalic, 568 
oxybenzoic. 422 
oxynaphtoic 422 
pannic, 118 (note) 
phosphoric, 566 
picramic, 426 
picric, 426 
piperinic, 72 
polygalic, 351 
propionic, 127 
pnissic,48, 68, 239 
pyrogallic, 107 
quillaiac, 35 1 
quinic, 357, 553 
quinonic, 367 ( note) 
ricinoleic, 99 
Balicylic, 391, LIS 
santoninic, 122 
Belenic, 7 < >7 
selenious, 7"7 
scleral inic, L8 ' 



738 



INDEX. 



Acid, sozoiodolic, 523 

sozolic, 422 

sphacelinic, 476 

sulfanilic, 516 

sulphuric, 564 

sulphurous, 566 

tannic, 111 

tartaric, 568 

telluric, 707 

trichloracetic, 568 

tropic, 279 

valerianic, 74 
Acids, 37, 559 

fatty, 567 

of the methane series, 129, 567 

organic, 567 
Acocanthera, 440 
Acoines, 314 
Aconine, 332, 336 

Aconite, comparison with antipyretics, 
388 

digitalis, 461 
Aconitine, 332 
Aconitum, 332 
Acorin, 70 
Action, cumulative, 28 

relation between chemical composi- 
tion and pharmacological, 24 

remote, local, indirect, general, 23 
Actol, 696 
Adeps, 50 

Lanse, 50 
Adhesive plaster, 88, 732 
Adipis, oleum, 51 
Adjuvants, 28 

Administration of drugs, 30 
Adonidin, 441 
Adonis, 440 
Adrenal extract, 463 
Adrenalin, 463, 466 
.Ether, 178 

aceticus, 181 
J^theris nitrosi, spiritus, 474, 476 
Affinity, elective, of drugs, 22 
Agaric, 301 
Agaricin, 301 
Agaricus, 301 

muscarius, 315 
Age in relation to dose, 25 
Agropyrum repens, 47 
Agrostemma, 351 
Ague, brass-founders', 688 
Airol, 699 

Alanin mercury, 658 
Alapurin, 50 
Albaspidin, 118 
Alcohol, 87, 128, 131 

amyl, 146 

butyl, 127, 146 

food value of, 141 

methyl, 128 

propyl, 127, 128, 146 
Alcohol-chloroform group, 127 
Alcoholic neuritis and arsenic, 611 

preparations, 39 



Alcoholism, chronic, 151 
Aldehyde, 129 

formic, 428 
Alkaline earths, see Calcium, Barium, 
Strontium 

carbonates, 544 

hydrates, 544 
Alkaloids, 35 
Alkasal, 702 
Allium, 68, 89 
Allspice, 68 
Almond, 239 

bitter, 68, 239 

oil, 51 

sweet, 48 
Aloe, 103 
Aloes, 100 
Aloin, 57, 101, 646 
Alsol, 702 
Althaea, 47 
Alum, (528, 700 

ammonioferric, 669 
Alumen, 702 
Aluminium, 700 
Alumnol, 702 
Amidocamphor, 430 
Ammonia, 555 
Ammoniacum, 88 
Ammonias, substituted, 503 
Ammoniated mercury, 657 
Ammonium acetate, 557 

bases, 50:5 

benzoate, 424 

bromide, 508 

carbonate, 555 

chlorate, 526 

chloride, 503 

citrate, 557 

iodide, 514 

salts, 261, 500 
Amygdala amara, 68, 239 

dulcis, 48 
Amygdalae, oleum expressum, 51 
Amygdalin, 48, 68, 239 
Amyl alcohol, 146 

nitrite, 468 
Amylamine, 727 
Amylene, 128 

hydrate, 128, 192,194 
Amylquinine, 261 
Amylum, 48 
Anacardium, 94 
Anacyclus, 73 
Anaesthesia, general, 154 

infiltration, 311 

local, 182, 311 

subarachnoid, 312 
Anaesthetics, general, 154 

local action of, 181 

mixtures of, 180 

preparations of, 178, 181 
Anagallis, 711 
Analgen, 374 
Anamirta, 436 
Andira araroba. 104 



INDEX. 






Anemone, 94 
Aneson, 129 
Anethi f ructus, 68 
Angostura bark, 59 
Anhalonium, 229 
Aniline, 35, 374, 428 
Animal extracts, 714 
Anion, 488 
Anise, 67 

oil of, 68 
Anisol, 391, 405 
Anodyne, Hoffman's, 181 
Antacids, 551 
Antagonistic effects, 29 
Anthelmintics, 117 
Anthemis, 67 

Anthracene purgatives, 100 
Anthraquinone, 101 
Anthrarobin, 104 
Antiarin, 441 
Antiaris, 440 
Antidote, the arsenic, 671 
Antifebrine, 374 
Antihydrotics, 302 
Antimoniuretted hydrogen, 637 
Antimony, 48, 625, 633 
Antinosin, 523 
Antipyretics, 373 
Antipyrine, 373 
Antiricin, 724 
Antiseptics, 393 
Antithermine, 374 
Antivenin, 726 
Antozon, 590 
Apalache tea, 246 
Aperients, 95 
Apocodeine, 237 
Apocynin, 441 
Apocynum, 440 
Apolysine, 375 
Apomorphine, 235 
Apple seeds, 239 
Aqua regia, 566 

Tofana, 607 
Aquae, 38 

of volatile oils, 70 

rosae, unguentum, 50 
Aqueous preparations, 38 
Arabin, 47 
Araroba, 104 
Arbutin, 77 

Arctostaphylos uva ursi, 77 
Argentamine, 695 
Argenti cyanidum, 244 
Argentic preparations, 694 
Argonin, 696 
Argyria, 693 
Aricine, 357 (note) 
Aristol, 523 
Aristolochia, 57, 59 
Aristolochine, 57 
Armoracia, 73, 89 
Amoraciae, Spir. Co., 69 
Arnica, 67, 68 
Arnicin, 70 



Aromatic bitter.-,. 70 

elixir, 69 

fluid extract, powder, 71 

series, 390 

spirit, 70 
Arsenate, iron, 671 
Arsenic, 607 

antidote, 671 

iodide, (J20 

sulphide, 620 
Arseniu retted hydrogen, 620 
Arsenous acid, 608 
Arsine, 620 
Artemisia, 122 
Asafoetida, 74 
Asagnea, 338 
Aseptol, 422 
Ash, flowering, 54 
Asiatic pill, 620 
Aspidin, 118 
Aspidinol, 118 
Aspidium, 118 
Aspidosamine, 356 
Aspidosperma, 356 
Aspirin, 391,419 
Asseline, 727 
Astragalus, 47 
Astringents, metallic, 628 

vegetable, 111 
Atropa, 280 
Atropamine, 280 
Atropine, 235, 279, 296, 330, 351 
Atroscine, 280 
Attar of roses, 68 
Aurantii cortex, 68 

vinum, 147 
Auri chloridum, 703 
Azulene, 62 

BML fruit, 60 
Balm, 67 
Balsam, 37, 39 1, 424 
Canada, 86 
copaiba, 76 
gurjun, 77 
of Peru. 424 
traumatic, 424 

of Tolu, 424 

Balsamodendron, B9 
Barbadoea nuts, 99 I note) 
Barbaloin, 1 01 

Barium. 440. 576 
Barley, 18 
Barosma, 7S 
Basham'a mixture, 672 

Baths. 195 

iron and steel, 
Hay. oil of, 
l'»;iy ruin. (»!> 

Bearben \ . 77 
Beaver, 136 
Bebeerine, 59 
Bebeeru bark. 
Bebirine, 59 
Beers, 1 17 



740 



INDEX. 



Belladonna, 280, 295 

plaster, 732 
Belladonnine, 280 
Bellatropine, 280 
Bengal quince, 60 
Benne, oil of, 51 
Benzaconine, 332, 336 
Benzanilide, 374 
Benzene, 390, 427 
Benzoates, 423 
Benzoic acid, 391, 423 
Benzoin, 424 

flowers of, 424 
Benzoinated lard, 50 
Benzol, 390, 427 
Benzoperacid, 592 
Benzoylecgonine, 302, 310 
Benzoylperoxide, 592 
Berberine, 56, 58, 59, 230 
Bergamot, oil of, 68 
Beryllium, 499 (note), 701 
Beta-eucaine, 313 
Betol, 391, 417 
Betulae, ol. vol., 68, 418 
Bhang, 233 
Biberine, 59 
Bicarbonates, 544 
Bichromate, 704 
Bile, 98, 712 
Birch, oil of, 68, 391, 418 
Bismuth, 628, 696 
Bitter almonds, oil of, 68, 239 
Bitters, 37, 56 

aromatic, 70 
Bittersweet, 351, 355 
Blackberry, 115 
Black draught, 103 

drop, 220 

wash, 657 
Blaud's pills, 670 
Blazing star, 351 
Bleaching powder, 587 
Blister, flying, 92, 732 
Blistering collodion, 92 
Blood, therapeutic use of, 673 
Bloodroot, 228 
Blue mass, ointment, 656 

pill, 656 
Blumea, 430 
Boletus laricis, 301 
Bone black, 581 

marrow, extract of, 723 
Bones, burned, 576 
Boracic acid, 582 
Boral, 702 
Borax, 582 
Boric acid, 582 
Borneo-camphor, 74, 430 
Borneol, 430, 433, 434 
Bornylamine, 430 
Boroglycerin, 583 
Bougies, 31 
Brandy, 72, 146 
Brassfounders' ague, 688 
Brassica, 90 



Brayera, 120 
Bromacetic acid, 129 
Bromal, 193 

Bromated camphor, 435 
Bromates, 529 
Bromelin, 711 
Bromides, 504 
Bromine, 586 
Bromism, 504 
Bromoform, 130, 180 
Bromol, 402 
Bromum, 587 
Broom, tops of, 267 
Brown mixture, 48, 220 
Brown-Sequard's fluid, 723 
Brucine, 196, 204 
Bryony, 105, 107 
Buchheim's classification, 42 
Buchu, 78 
Buckthorn, 103 
Bufonin, 440 (note) 
Bufotulin, 440 (note) 
Bunge's theory of iron, 662 
Burgundy pitch, 86 

plaster, 732 
Burnett's solution, 691 
Butternut, 108 
Buttonbu.sh, 427 (note) 
Butyl alcohol, 128 

chloral, 129, 192, 194 
Butylamine, 727 
Butyrates, 554 
Butyric acid, 129 
Buxine, 56, 59 

CACAO, 245 
butter, 31,40, 255, 731 
Cachets, 41 

Cacodylates, 622 (note) 
Cacodylic acid, 608 
Cactaceae, 229 

Cactus grandiflorus, 440 (note) 
Cade, oil of, 410 
Cadmium, 706 
Caesium, 499 
Caffeine, 245 

compared with atropine and 
strychnine, 282 
Cajuput, oil of, 68, 406 
Calabar bean, 196, 324, 328 
Calabarine, 196, 204, 324 
Calamus, 70 
Calcis, liquor, 574 
Calcium, 569 

bromide, 508, 576 

carbonate, 575 

chloride, 574 

glycerophosphate, 576 

hydrate, 574 

hypochlorite, 587 

hypophosphite, 534 

lactophosphate, 576 

peroxide, 593 

phosphate, 576 

sulphate, 576, 732 



INDEX. 



741 



Calcium sulphide, 579 

Calefaciens, emplastrum, 732 

Cali nut, 324 

Calomel, 655 

Calumba, 58 

Calumbin, 56, 57 

Calx, 574 

chlorata, 587 

sulphurata, 579 
Cambogia, 107 
Camphor, 430 

com. tincture, 221 

monobromated, 430, 508 
Camphoric acid, 302, 430, 433, 435 
Camphorol, 430, 433 
Canada balsam, 86 
Canadian hemp, 440, 457 

moonseed, 59 
Canadine, 56, 230, 231 
Cane sugar, 54 
Cannabin, 235 
Cannabinol, 233 
Cannabis Indica, 233 
Canquoin's paste, 690 
Cantharidin, 90 
Cantharis, 91 
Caoutchouc, 732 
Caprylates, 554 
Capsicum, 72, 94 
Capsules, .31, 41 
Capsule, suprarenal, 463 
Caraway, 68 
Carbo, 581 

Carbolic acid, 390, 398 
Carbon, 581 
Carbonates, 544 
Carbonic acid, 584 
Carbylamine, 240 
Cardamom, 68 
Cardol, 94 
Carica, 711 
Carlsbad salts, 541 
Carminatives, 63, 72, 74 
Carniferrin, 673 
Carolina Jasmine, 265 
Carragheen, 48 
Carron oil, 575 
Carum, 68 
Caryophyllum, 68 
Caryophyllus, 68 
Casca bark, 440 
Cascara sagrada, 104 
Cascarilla, 70 
Cassia acutifolia, 102 

angustifolia, 102 

fistula, 54 

purging, 54 
Cassiae pulpa, 54 
Castanea, 115 
Castile soap, 731 
Castoreum, 436 
Castor oil, 99, 724 
Catalase, 592 

Cataplasma,41 (See Poultices) 
Catechu, 114 



( iathartics, 95 

saline, 535 
Cathartin, 101 
Caulophyllum, .'555 
Caustic, lunar, 694 

mitigated. 69 \ 

potash, 549 

•soda, 549 

toughened. 094 
Cayenne pepper, 72 
Celandine, 228 
Cephseline, 343 
Cephadis, 343 
Cephalanthin, 427 (note) 
Cera, 51, 731 
Cerates, 30,40, 731 
Ceratum, 51 

camphorte, 87 
Cerberin, 44 1 
Cereus, 440 (note) 
Cerium, 700 
Cetaceum, 5 1 
Cetraria, 48 
Cetraric acid, 48, 59 
Cetrarin, 57 
Cevadilla, 338 
Cevadilline, 338 
Cevadine, 338 
Cevine, 338 
Chalk, 575 

Chalybeate preparations, <i»i'.» 
Chamyelirium, 351 
Chamomile, 67 
Champagne, 147, 584 
Charas, 233 
Charcoal, 581 
Charta, 41 
Chaulmoogra, 94 
Chavicine, 72 
Chavieinic acid, 72 
Cheiranthin, 441 
Cheiranthus, 441 
Chelerythrin, 228 
Chelidonine, 228 
Chelidoiiium,228 

Chemical composition and action, 24 
Chenopodiuin, 126 
Cherry, Virginian, 68, 240, 244 
Cherry water, 72, 147 
Chestnut, 115 
children, dose for, 25 
Chili saltpeter, 532 
Chillies, 73 
Chimaphila, 7^> 
Chinotropini 
Chirata,59 
Chiretta, 50 
Chloracel ic acid, [29 
Chloral, 129, is:. 193 

compared with hyoscin< 
Chloralamide, L29, i!'J. L94 
Chloralose, 129, l" ::. 194 
Chlorates, 526 
Chloretone, 129, 193, 194 
Chlori aqua 



742 



INDEX. 



Chlorides, l!i<) 
Chlorinated lime, 587 

soda, 587 
Chlorine, 580 
Chlorodyne, 181,222 
Chloroform, 71, 118,120,164,178,181 
Chlorphenol, 392, 402 
Chlorum, 587 
Chocolate, 245, 255 
Cholagoguea, 95, 714 
Chondrodendron, 59 
( ihondrus, 48 
Christinas rose, 440 
Chromic acid, 594, 704 
Chromium, 704 
Chromotherapeutics, 428 
Chrysarobin, 104 
Chrysophanic arid, 101, 104 
Chrysotoxin, 477 
Churrua, 233 
Cicuta, 430 
Cicutoxin, 436 
Cinchona, 357 

red, 357 (note) 
Cinchona mine. 357 (note) 
Cinchonidine. 357 
Cinchonine, :!." ( 7 
Cineol, L22 
Cinnamie acid, 301 
Cinnamoinuni camphora, 430 
Cinnamon, 68 
Cinnamyl-coeaine, 302 
Citrates, 535, 539 
Citric acid, 569 
Citrine ointment, 658 
Citrophen, 375 
Citrullus colocynthis, 106 
Clarets, 147 

Classification of drugs, 41 
Claviceps purpurea, 476 
Cloves, 68 
Clysma, 41 
Clyster, 41 
Coal-tar, 410 
Cobalt, 706 
Coca, 302,310 
Cocaine, 302, 309, 427 
Cocainization, intra-spinal, 312 

subarachnoid, 312 
Cocamine, 302, 309 
Coccu?, 55 
Cochineal, 55 
Cochlearia, 73, 89 
Cocoa, 245 
Codamine, 207 
Codeine, 207, 217, 221 
Cod-liver oil, 726 
Coffee. 245, 254 
Coffeon, 254 
Cohosh, blue, 355 
Cola, 245 
Colchicum, 347 
Cold, 86 

bath, 387 

cream, 50, 70 



(old pack, Wli 

( oleoptera, 91 
Colic, painter's, <i~7 
( lolica Pictonum, «i77 

-at in ii ilia . 1177 

Collodia, 30, i<», 732 
( !olloid subatancea, 15 

as demulcents, 45 
:i- purgatives, ~>i 
relal iona of i<* -alt 
Collodium, .'><>, 40, 732 

-1 \|it irlllll. 1 11, ~.vi 

veaicana, 92, 732 
Colloxylin, 732 
Colocynth, LOS 
( lologne, caii de, 69 
( lolophonj . B8 
Columbo, 58 
( iommiphora, B9 
( lommon salt , 490 
Coniprcss<'s, hot water, 86 
( loncuaconine, .'!~>7 | note) 
Condurango, 57. 59 
Condy'e fluid, 594 
Confcct iones, 10 
Conhydrine, 262 
Coniine, 261, 330 
Conium, 202 

( on jmict i\ a. applications 1<>. 31 
Conquairamidine, 357 (note) 
Conquairamine, 357 (note) 
Conquinamine, 357 (note) 
Conquinine, 357, 366 
Convallamarin, 441 
Convallaria, 440 
Convolvulin, 105 
Convolvulus, 107 
Copaiba, 75 
Copaiva, 75 
Copper, 327, 628, 684 

a rsenite, 607 
Coral, 576 
Coralline, 576 
Coriamyrtin, 436 
Coriander, 67 
Coriaria, 436 
Corncockle, 351 
Cornsilk, 78 
Cornsmut, 483 
Cornutine, 476, 482 
Coronilla, 440 
Coronillin, 441 
Corrosive sublimate, 654 
Cotarnine, 230, 23- 
Coto bark, 58, 59 
Cotoin, 58, 59 
Cottonroot bark, 483 
Cottonseed oil, 51 
Couchgrass, 47 
Counter-irritation, 78 
Court plaster, 732 
Cranesbill, 115 
Orede's colloid silver, 696 
Creolin, 405 
Creosols, 391, 412 



INDEX. 



■4:; 



Creosote, 392, 411 
Cresalol, 391, 417 
Cresol, 391, 404 
Cresotinic acid, 391 
Greta, 575 

pulv. cum opio, 221 
Crocus, 55 
Crotin, 725 

Croton-chloral, 129, 192 
Croton oil, 99 
Crotonoleic acid, 99 
Croton Tiglium, 100, 725 
Cruciferee, oils of, 61, 72, 89 
Cryptopine, 207, 219 
Cubebin, 75 
Cubebs, 76 

Cucumber, squirting, 107 
Cucurbita, 122 
Culver's Root, 107 
Cumarin, 524 
Cumulative effects, 28 
Cupratin, 687 
Cuprea, 357 
Cupric sulphate, 687 
Cuprohsemol, 686 
Curacoa, 72 
Curara, 256, 330 
Curarine, 256 
Curd soap, 731 
Curine, 256, 260 
Currier's sumach, 436 
Cuscamidine, 357 (note) 
Cuscamine, 357 (note) 
Cusconidine, 357 (note) 
Cusconine, 357 (note) 
Cusparia, 59 
Cusso, 120 
Cutol, 702 
Cuttlefish, 576 
Cyanides, 240 
Cyanogen, 240 
Cyclamen, 351 
Cynoctonine, 336 
Cypripedium, 68 
Cytisus scoparius, 266 

DANDELION, 59 
Daphne mezereum, 94 
Datura, 281, 295 
Daturine, 280 
Dead tongue, 436 
Decocta, 39 
Decoctions, 39 
Degeneration, fatty, 596 
Delirium tremens, 151 
Delphinium, 332 
Demulcents, 45 
Depression, depressants, 20 
Derivation, theory of, 79 
Dermatol, 699 
Dermol, 700 
Desoxycaffeine, 254 
Dextrins, 45 
Diacetylperoxide, 592 
Diachylon ointment, 50 



Diachylon plaster, 682, 732 
Diastase, 711 
Didymium, 499 (note) 
Diffusion, 485 
Digestive ferments, 709 
Digitalein, 441 
Digitalin, 441 
Digitalines, 456 
Digitaliresin, 436 
Digitalis, 351, 436, 440 

comparison with aconite, 337 

with antipyretics, 388 
Digitonin, 351,441 
Digitophyllin, 441 
Digitoxin, 441 
Dihydrolutidine, 727 
Dill, 68 
Dionea, 711 
Dionine, 218 
Diosphenol, 78 
Dioxide of hydrogen, 591 
Dipterocarpus alatus, 77 
Discs, 40 

Disease, effect of, on dose, 29 
Disinfectants, 393 
Dissociation of salts, 488 
Diterpenes, 61 
Diuretin, 252 
Dock, 115 

Dogwood, 427 (note) 
Donovan's solution, 620, 655 
Dorema ammoniacum, 88 
Dormiol, 192 

Dose, conditions modifying the, 25 
Dover's powder, 220, 346 
Drastics, 95 
Dropwort, vvater, 436 
Drosera, 711 
Drugs, 17 

action of, 20 

chemical character of, 34 

classification of, 41 

conditions modifying the effect of, 
25 

definition of, 17 

elective affinity of, 22 
Dryobalanops, 430, 434 
Dryopteris filix-mas, 119 
Duboisia Hopwoodii, 280 

myoporoides, 280, 281 
Duboisine, 280, 294 
Dulcamara, 351, 355 
Dulcamarine, 351 
Dulcin, 55 

Dusting powders, 53 
Dyes, aniline, 428 

UASTON'S syrup, 307 

Vj Eau do cologne, 69, 146 

Eeballium, 107 

Eccoprotic, 95 

Ecgonine, 302, 310 

Effects of drugs, conditions affecting, 

Effervescing purgatives, 541 



744 



INDEX. 



Egg, yolk of, 4!) 

Eigon, 520 

Elastica, 732 

Elaterin, 105 

Elaterium, 105, 107 

Elderflower, <>7 

Elecampane, i!» 

Eled ive affinity of drugs, 22 

Elecl uaries, 40 

Elemi,89 

Elixirs, 30 

aromatic, 69 
Elm, slippery, 47 
Eloeoptene, 61 
Embrocal inns, 40 
Emetics, 238 
Emetine, 343 
Emodin, 101 
Emollients, 40 
Emplastra, 30, 41, 731 
Emplastrum calef aciens, 02, 732 
Emulsa,39 
Emulsin, 48, 68, 230 
Emulsions, 32, 39 
Endermic, 33 
Enema, 31, 41 
Epinephrine, 440, 403 
Epsom sails, 535 
Erbium, 4!)'.) (note) 
Ergochrysin, 477 
Ergol . I7t> 
Ergotin,482 
Ericolin, 77 
Erigeron, oil of, 68 

lull lines, 31 

Erythrol, tetranitrate, 469, I7i 
Erythrophceine, 441 
Erythrophlceum, 440 

Erythroxylon, 310 
Eseridine, 324 
Eserine, 324 
Essences, 71 

of volatile oils, 69 
Essential oils, 61 
Esters, 129 
Ether, 71, 129, 154, 178 

acetic, 71, 181 

nitric, 468 

nitrous, 468 
Ethereal oils, 61, 86, 392 

salts, 129 
Ethyl alcohol, 128 

biomide, 130, 179 

chloride, 182 

ether, 129 

nitrite, 65, 474 

oxide, 178 
Ethylene bromide, 180 

chloride, 129, 179 
Ethylidene chloride, 129, 179 
Eucaine, 313 
Eucalypti gummi, 115 
Eucalyptol, 71, 406 
Eucalyptus, 67, 68 

oil of, 68, 406 



Eudoxine, 523, 700 
Euonj mm, lo;,, 1 1 1 
Euonj mil-, 105, 107, 441 
Eupborbin, '.» i 
Euphorin, .'575 
Euquinine, 368 
Europhen, ■>-■'> 
Euroi nun orj hb, 7 12 
Exalgine, -''.7 1 
Extracts, 40 

anima I, 7 1 1 

fluid, liquid, :;!> 
Extractum aromaticum fluidum, 71 

i \r.L\.\.\.7M 

I 1 Fats, L0 

i';iti \ degeneraf ion, .")!)<) 

I .I Boris, 714 

Fennel, 68 

Fermenl b, digest ive, 709 

Ferratin, <i7.'{ 

Fen ic preparal ions, 660 

salts i See 1 1 1 
I'm rocyanides, ~± L0, 
Ferroua pirji.tiiiti.ui-. 660 
Fei ruginoufl preparations, 670 
Ferula, 74 

galbanum, 88 

FicUS, 55 

Fim, r,,->. 711 
Filicic acid, 118 
l'ili\ mas, 118 
Flag, blue, 107 
Flavaspidic acid, 1 18 
Flavoring Bubstances, 54 
Fleabane, 68 
Flexible collodion, 732 
Flowering ash, 54 
Flowers o! sulphur, 50 
Fluorides, 525 
Flying blister, 92 
Foeniculum, 68 
Formaldehyde, 394, 428, 533 
Formaline, 428 
Formates, 554 
Formic acid, 568 
Fowler's solution, 620 
Foxglove, 440 
Frangula, 100, 103 
Frangulin, 101 
Frankincense, 86 
Fraxinus, 54 
Friar's balsam, 424 
Fruit juices, 563 
Frumenti, spiritus, 146 
Fuller's earth, 53 
Fumigation, mercurial, 652 
Fusel oil, 146 

f\ ADUS, 726 

IT Galbanum, 73, 88 

Galipine, 59 

Galla, 115 

Gallacetophenone, 408 

Galla?, ung. cum opio, 222 



INDEX. 



740 



Gallal, 702 

Gallic acid, 111, 114 

Gamboge, 107 

Ganja, 233 

Garcinia, 107 

Gargarisma, 31 

Gargle, 31 

Garlic, 68, 89 

Gas, laughing, 183 

Gaultherise, oleum, 68, 418 

Gelatin, 574 (note) 

capsule, 41 
Gelsemine, 196, 204, 265 
Gelsemium, 261, 265 
General action, 23, 31 

anaesthetics, 154 
Genito-urinary disinfectants, oils used 

as, 75 
Gentian, 58 
Geranium, 115 
Gigartina, 48 
Gila monster, 725 
Gin, 72, 146 
Ginger, 68, 72 
Gland extracts, 715 
Glauber's salt, 535 
Glonoinum, 474 
Glucose, 54 
Glucosi, syrupus, 54 
Glucosides, 36 
Glusidum, 55 
Glutol, 430 
Glycerin, 40, 51 
Glycerin trinitrate, 468 
Glycerites, 40 
Glyceritum amyl, 51 

vitelli, 51 
Glycerophosphates, 543, 576 
Glycol, 127 
Glyconin, 51 
Glycosides, 36 
Glycyrrhiza, 48 

compound mixture, 220 
Glycyrrhizin, 48 
Gnoscopine, 207 
Goa powder, 104 
Gold, 703 
Golden seal, 230 
Gonolobus, 59 
Gorite, 593 
Gossypii, radicis cortex, 483 

seminis, ol., 51 
Goulard's extract, cerate, lotion, 682 
Granatum, 121 
Grape cure, 563 
Gray oil, 657 

powder, 656 
Greens, Scheele's, Schweinfurt's, Paris, 

607 
Gregory's powder, 102 
Grey oil, 657 

powder, 656 
Griffith's mixture, 670 
Guaiacol, 391, 412 

carbonate, 391, 412 



Guaiacol salol, 417 
Guaiacum, 88 
Guanine, 254 
Guarana, 245 
Gum, 37, 45 

arabic, 47 
Gum-resins, 37 
Gun cotton, 732 
Gurjun balsam, 77 
Gymnema silvestre, 306 (note) 
Gymnemic acid, 306 ( note ) 
Gynocardia, 94 
Gypsophila, 351 
Gypsum, 576, 732 

H^MATOGEN, 673 
Hsematoxylon, 115 
Haemogallol, 673 
Haemoglobin, 673 
Hssmol, 673 
Hagenia, 120 
Hamamelis, 115 
Harnack's experiment, 327 
Hartshorn, spirit of, 556 
Hashish, 233 
Heat, 86 

Heavy metals, 625 
Hedeoma, 68 
Hedonal, 129, 192, 194 
Hellebore, green, white, 338 
Helleborein, 441 
Helleborus niger, 440 
Heloderma, 725 
Hemidesmus, 355 
Hemlock, 262 

water, 436 
Hemp, Canadian, 440, 457 

Indian, 233 
Henbane, 281 
Hepar sulphuris, 579 
Heroine, 217 
Hesperidin, 70 
Heteroxanthine, 246 
Hexylamine, 727 r^- 
Hock, 147 

Hofmann's anodyne, 181 
Holocaine, 314, 389 
Homatropine, 280, 294, 20(1 
Homococamine, 302 
HomochelidoniiK', 228 
Homocinchonidine, 357 mote) 
Homoisococamine. 303 
Honey, 39, 54 
Hops, 58 
Hordeum, 48 
Horehound. Ii7 
Horseradish, 69, 73,89 
Hot compresses 

packs. 322 
Humulus, 59 
1 [unjadi-janos, 6 1 1 
Hydragogu< 
I [ydrargyrum, 65 I 
Hydrastine, 230, 231 
Hydrastinine, 230, 231 



Hi 



INDEX. 



Hydrastis, 
Hydrates, 54 I 
Hydriodic acid, 514 
Hydrobromic acid, 608 
l [ydrochloric acid, 665 

I Lydrocinchonine, •'!-">7 | note | 

I I \ droootarnine, -"7, 2l.s 
I Is drocj anic arid, 230 

1 1 j dronuoric acid, 525, 567 
I [ydrogen, anl Lmoniuretted, 687 

B i -tiiiui el ted. 02U 
dioxide, .".!tl 

ion, 559 
peroxide, "> u i 
phosphuretted, 605 
Bulphuretted, 579 

I [ydroquinidine, 357 I note | 

I I \ droquinine, 357 I not* | 
Hydroquinone, 77, 390 
Hydroaulphuric acid, 579 
Sygrine, 303 | note I 

1 1> oacine, 279, 293 
Hyoacyamine, 235, 279, 292, 296 

I [yoscyamus, 28 I 

I I j pertonic boIuJ ions, 186 

llypnal. 193, 37 I 

Hypnone, L29, 193 

1 1 \ pilot ics, I s7 

I [ypochloritea, 587 

I [ypodermic injed ion, 83 

I [ypophoephitea, 53 I 

1 1\ pophysia, exi pad of, 722 

Hypoquebrachine, 356 

ll\ posulphitea, 53 I 

Hypotonic solution, 486 

ICELAND mosa, 48, 59 
Ichthyocolla, 732 
[chthyol, 392, 412 
Idiosyncraaiea, 27 

Ignatia, 204 
Ilex, Paraguay, 245 
Illicium, 68 
Immunity, 28,725 
Indian corn, 78 

hemp, 233, 235 

tobacco, 278 
India-rubber, 732 
Indirect action, 23 
Infiltration anaesthesia, 311 

fatty, 596 
Infundibular body, 722 
Infusa, 39 
Infusions, 39 
Ingluvin, 711 
Injection, hypodermic, 33 

intravenous, 34 

subcutaneous, 33 
Insect poisons, 725 
Internal secretions, 714 
Intestine, absorption from, 32 
Intraspinal cocninization, 312 
Intravenous injection, 34 
Inula, 49 
Inunction. 33, 650, 657 



[odalbumii 
[odates, 529 
[odides, 510 
[odine, 517, 7 1:» 

pin, 520 
[odiam, 510 
[odofoi iii. 52 1 

lodol 

[odolen, 520 
[odoepongin, 720 

lodot !i\ fiii. 7 15 
lodiiiu, 519 
[one, 188 
[peeacuanha, 8 

I pi ••-. M ii. uili. i- pull i- « o , 221 

CUID -«• i 1 1 :i . pit. 221 
Ipoinui. I m7 
[ris, 107 

I ri-li in" — , is 

Hon, 828, I 

arsenate, 621 

\\\ pophosphitc 
I .i it .it ion, In it. nit - 
[rritants, akin, 7^ 
[ainglaaa, 732 
[eoamyl alcohol, tertiarj 
[aobuty] nitrite, 472 
I sococamine, -i^~ 
[aolichenin, I s * 
Uonit riles, 2 io 
[aopellel ierine, 121 
I Bopilocarpine, •'! 15 
[soquinoline, 35, 264 
Isotonic solut ions, 486 
Itrol. 696 
i\y. poison, 

r ABORANDI, 315, 321 
n Jaborine, 31 5 | note) 
Jalapa, L07 
Jalapin, 105 
James' powder, 637 
Japaconif inc. 332 
Jaamine, yellow or Carolina, 265 
Jateorhiza, 58 
Jatropha, 90 (note) 
Javelle's solution, 587 
Jecoris aselli. oleum, 728 
Jequirit v. 72.1 
Jervine,'338 
Jesuit's drops, 424 
Juglans, 108 
Juices, 40 
Juniper, empvreumatic oil of, 410 

oil, 68 

sabina. 87 

tar oil, 410 

KAIRIXE, 374 
Kairoline, 374 
Kali nut, 324 
Kamala, 122 
Kaolin, 53,731 
Kation. 488 
Kava-kava, 73 



INDEX. 



Ill 



Keratin, 731 
Kermes mineral, 637 
Ketones, 129 
Kino, 115 

pulvis comp., 221 
Kirsehwasser, 72 
Kola, 245 
Kombe, 440 
Kosin, 120 
Kosotoxin, 120 
Kousso, 120 
Krameria, 114 
Kresamine, 405 
Kryoflne, 375 
Kummel, 72 

T ABARRAQUE'S solution, 587 

jL Lactates, 554 

Lactation, medication during, 26 

Lactic acid, 568 

Lactophenine, 375 

Lactophosphate, 576 

Lactose, 54 

Lactuca, 235 

Lactucarium, 235 

Lady's slipper, 68 

Lamellae, 40 

Lanichol, 50 

Lanolin, 50 

Lanthanum, 499 (note) 

Lanthopine, 207 

Lappaconitine, 336 

Lard, 50 

oil of, 51 
Largin, 696 

Larynx, application to, 31 
Laudanine, 207, 219 
Laudanosine, 207 
Laudanum, 220 
Laughing gas, 183 
Laurel, 68, 240 

camphor, 434 

leaves, 68, 240 

water, 70 
Laurocerasi folia, 68, 70 
Laurocerasus, 240 
Lavender, oil of, 68 
Laxative, 95 
Lead, 628, 674 

iodide, 514 

palsy and arsenic, 611 

plaster, 732 
Lemon, 68 

essential salts of, 569 

juice, 569 

oil of, 68 
Leptandra, 107 
Leptandrin, 105 
Lettuce, 235 
Levico water, 621 
Lichenin, 48 
Lily of the valley, 440 
Lime, 569, 574 

chlorinated, 587 

hypophosphite, 534 



Lime juice, 569 

phosphate, carbonate, 53 

sulphurated, 579 
Limonis cortex, 68 
Liniments, 40 
Linimentum camphoras, 87 

chloroformi, 87 

saponis, 87 
Lini oleum, 51 
Linseed, 47 

oil, 51 
Linum, 47 
Lipanin, 728 
Liqueurs, 67, 71 
Liquidambar, 424 
Liquid extracts, 39 
Liquor epispasticus, 92 
Liquores, 39 
Liquorice, 48 
Litharge, 682 
Lithium, 499 

benzoate, 424 

bicarbonate, 544 

bromide, 508 

carbonate, 544 

citrate, 540, 541 

hydrate, 544 

salicylate, 418 
Liver of sulphur, 579 
Lizard, poisonous, 725 
Lobelia, 278 
Lobeline, 278 
Local action, 23 

ana;sthesia, 182, 311 
Logwood, 115 
Loretin, 523 
Losophan, 523 
Lotions, 39, 657 
Lozenges, 31, 40 
Lugol's solution, 519 
Lunar caustics, 694 
Lungs, absorption from, 32 

administration by, 30 
Lupulin, 59 
Lupulinic acid, 58 
Lupulus, 59 
Lycaconitine, 337 
Lycetol, 553 
Lycopodium, 53 
Lysidine, 553 
Lysol, 405 
Lytta, 91 

MACE, 68 
Magisterium bismuthi, 698 
Magnesia, 540, 550 

fluid, 540 
Magnesium. 539 

' carbonate, 535, 550 
chloride, 
citrate, 535, ■ \\ 

oxide. G 
salts. 539 
sulphate, 
Maize, 7^ 



748 



INDEX. 



Maize, fungus of, 483 
Malakine, 375, 417 
Malates, 535 
Male fern, 118 
Mallotus, 122 
Malonates, 558 
Malt enzyme, 711 

extract, 711 
Maltine, 711 
Maltzyme, 71 1 
Mandragora, 281, 295 
Mandragorine, 280 
Mandrake, 280, 281, 295 
Manganese, 628, 703, 705 
Mangani dioxidum, 705 
Manieheel tree, 94 
Manna, 54 

Mannitol hexanitrate, 469 
Marrubium, 67 
Marshmallow, 47 
Massa, 40 
Mastiche, 103 
Mate, 245 

Materia medica, definition of, 19 
Matico, 77 
Matricaria, 67 
Maydis, uatilago, 483 
Meals, influence of, on dose, 26 
Meconic acid, 207 
Meconidine, 207 
Medicated waters, 38 
Medication, local, 30 
Mel, 54 
Melissa, 67 
Mellita, 39 
Menispermum, 56, 59 

cocculus, 436 
Menstruation, 26 
Mentha, 67 
Menthane, 430 

Menthol, 71, 430, 434, 732 , 
Mercurial ism, 641 
Mercury, 625-632, 638 

iodide, 514, 655 

sozoiodolate, 523, 658 
Metacresol, 404 
Metals, heavy, 625 

minor, 703 
Metaphosphates. 539 
Methacetine, 375 
Methyl alcohol, 128 

-arbutin, 77 

bromide, 180 

chloride, 182 

coniine, 262 

hydroquinone, 77 

morphine, 218 

salicylate, 391,417,418 

strychnine, 261 
Methylal, 129 
Methylene bichloride, 179 
Meyer-Overton theory of narcosis, 

128,167 
Mezcal buttons, 229 
Mezcaline, 229 



20, 



Mezereum, 94 
Milk of lime, 576" 

sugar of, 64 

of sulphur, 580 

Mindererus, spirit of, 557 
Mineral waters, 570, 588, «J7:J 

alkaline, 552 

iron, 071 
.Mint, essence of, 72 

Mistime, ,'i!) 
Mil lniil.il ism, 27 
Mitigated caustic, 694 
Mixture, 39 

brown. IS 
Molasses, 54 

Molybdenum, 706 

Monkshood, 337 

Monobromated camphor, 430, 434, 508 

Monochlorphenol, 391, 402 

Monsel's solution, (i(i!» 
Moonseed, < lanadian, 59 
Morphine, 207, 219 

comparison wit li antipyrine 

poisoning, atropine in, 29!) 
Mm phinism, 226 
Morpholine, 207 
MorrhusB, oleum, 728 
Morrhuine, 727 
Morrhuol, 728 
Moschus, 4:55 

Mouth, administration by, 30, 31 
Muawine, 442 
Mucilage-, 39, 47 
Mucuna, 324 
Muriatic acid, 565 
Muscale buttons. 229 
Muscarine, 315, 330 
Mushroom-. :il ."> 
Musk, 74, 435 
Mustard, 72, 89 
Myoctonine, 337 
Myrcise oleum, 68 
Myriapoda, 239 
Myristica, 68 
Myronate, 89 
Myrosin, 89 
Mvroxvlon, 424 
Myrrha, 89, 103 

NAPHTHALAN, 392 
Naphthalene, 390, 408 
Naphtalol, 417 
Naphtol, 118, 390, 408 
Naphthylamine. 426 
Narceine, 207, 218 
Narcosis, Maver-Overton theory of, 20, 

128, 167 
Narcotics, of methane series, 127, 187 
Narcotine, 207, 218, 230 
Nectandrae cortex, 59 
Neriin, 441 
Neriodorin, 441 
Nerium, 440 
Neroli, oil of, 68 
Neurodine, 375 



INDEX. 



749 



Newt, 437 
Ngai-camphor, 430 
Nickel, 706 
Nicotiana, 268 
Nicotin, 268, 330 
Nightshade, black, 351 

deadly, 280 
Nitrates, 468, 531 
Nitre, 532 

sweet spirits of, 474 
Nitric acid, 565 

ethers, 468 
Nitriles, 240 
Nitrites, 468 
Nitrobenzol, 425 
Nitro-bodies, 469 
Nitroethane, 469 
Nitroglycerin, 468, 473 

and digitalis, 460 
Nitrohydrochloric acid, 565 
Nitromethane, 469 
Nitrous ether, 468 

oxide, 183 
Nose, application to, 31 
Nosophen, 523 
Nut-gall, 115 
Nutmeg, 68 

Nuts, purging, 99 (note) 
Nux vomica, 196, 204 

OAK BARK, white, 115 
poison, 93 
Octane, 128 

Oenanthic ethers, 72, 131, 146 
Oenanthotoxin, 436 
Oenanthylates, 554 
Oil, See Oleum 
Oil, cod-liver, 725 

cotton-seed, 51 

fusel, 146 

of roses, 68 
Oils, 49, 51 

essential, 61, 392 

ethereal, 61 

purgative, 91 

volatile, 61, 392 
Ointments, 30, 40, 50 
Olea, 51 
Oleander, 440 
Oleandresin, 436 
Oleandrin, 441 
Oleates, 40 
Oleites, 356 

Oleoresin zingiberis, 68 
Oleoresins, 37 
Oleum adipis, 51 

amygdalae amarse, 68, 239 
expressum, 51 

anethi, 68 

anisi, 68 

aurantii florum, 68 

ber^amottae, 68 

betulae volatile, 68, 418 

cadinum, 410 

cajuputi, 08 



Oleum carui, 68 
caryophylli, 68 
clienopodii, 126 
cinereum, 657 
cinnamomi, 68 
copaiba', 76 
coriandri, 68 
crotonis, 99 
cubebae, 76 
erigerontis, 68 
eucalypti, 68 
foeniculi, 68 
gaultheriaj, 68, 418 
gossypii seminis, 51 
hedeomae, (is 
jeeoris aselli, 728 
juniperi, 68, 87 
lavandulae florum, 68 
limonis, 68 
lini, 51 
menthse piperitae, 68 

viridis, 68 
morrhuaBj 728 
myrciae, 68 
myristicae, 68 
olivae, 51 

phosphoratum, 605 
picis, 410 
pimentae, 68 
pini, 87 
ricini, 99 
rosae, 68 
rosmarini, 68 
sabinae, 68, 87 
santali, 76 
sassafras, 68 
sesami, 51 
sinapis volatile, 90 
terebinthime, 86 
theobromatis, 731 
tbvmi, 68 
tiglii, on 
Olive oil, 51, 728 
Oophorin, 723 
Ophelic acid, 59 
Opianic acid. 230 
Opium, 207. 219 

comparison with liy-ucine, 300 
Orange flowers, oil ol 
pod. 68 
wine. 1 17 
Ordeal bean. 324. 328 
Orexine, 58, 60 
Organic acids, 567 

iron, <>~>'- ) 
Organotherapeul ics, 71 I 
Orphol, 7(H) 
Orpiment, 607 
Orthocresol, i" 1 "' 
Orthoform, 31 i 
Orthopbosphates, 589 
Oscine, 279 
( ><mic acid, 7<>7 
Osmosis, 186 
Osmotic pressure, i <|- ' 



750 



INDEX. 



Otto of roses, 68 
Ouabaio, 440 
Oxalates, 557 
Oxalic acid, 568 
Oxamine, 558 
Oxgall, 714 
Oxybenzoic acid, 422 
Oxydimorphine, 217 
Oxygen, 588 
Oxymel, 39, 54 
Oxynaphtoic acid, 391, 422 
Oxynarcotine, 207 
Ozone, 590 

PACK, hot, cold, 322 
Palmitatis, 554 
Palsy, painters', 678 
Panama bark, 355 
Pancreas, extract of, 723 
Pancreatic ferment, 710 
Pancreatin, 710 
Pannic acid, 118 (note) 
Papain, 711 
Papaja, 711 
Papaveraceae, 228 
Papaveramine, 207 
Papaverine, 207, 218 
Papaveris capsular, 222 
Papaver Rhoeas, 55 

somniferum, 207, 220 
Papayotin, 711 
Papers, 41 
Papoid, 711 
Paracotoine, 58 
Paracresol, 405 
Paraffin, 50 
Paraform, 429 
Paraguay tea, 245 
Paraldehyde, 129, 191, 194 
Paralysis, definition of, 21 

and fatigue, relation between, 257 
Paramidophenol, 374 
Paraxanthine, 246, 254 
Paregoric, 220, 434 
Pareira, 59 
Parilla, yellow, 59 
Parillin, 351 
Paris green, 607 

plaster of, 576, 732 
Pathological conditions modifying dose, 

29 
Paullinia, 245 
Pawpaw. 711 
Payta, 356 
Paytanine, 356 
Pearson's solution, 620 
Pelletierine, 121 
Pellitory, 72 
Pellote, 229 
Pennyroyal, 68 

oil, 68 
Pental, 128, 179 
Pentane, 128 
Pepo, 122 
Pepper, 72, 94 



Pepper, black, 72 
Cayenne, 72 

Peppermint, 67 
oil of, 68,420 

Pepsin, 70!) 

Peracids, 592 

Perchlorates, 529 

Perchlorethane, 180 

Permanganates, 593 

Peronine, 218 

Peroxide of hydrogen, 591 

Persodine, 593 

Persulphates, 593 

Peru, balsam of, 424 

Petrolate, 50 

Petroleum, 50 

Peyotl, 229 

Pharmacognosy, 19 

Pharmacological action and chemical 
structure, 24 

Pharmacology, definition of, and rela- 
tions to biology and clinical subjects, 
17-19 

Pharmacopoeia, 37 

Pharmacy, 19 

Pheasant's eye, 440 

Phenacetine, 375 

Phenanthren, 207 

Phenatidines, 375 

Phenazone, 385 

Phenetol, 391,405 

Phenocoll, 375 

Phenol, 390, 398 

Phenylhydrazine, 374 

Phloretin, 730 

Phloridzin, 729 

Phosphates, 535, 539 

Phosphidum zinci, 605, 690 

Phosphine, 605 

Phosphorated oil, 605 
! Phosphoric acid, 566 

Phosphorus, 594 

Phosphuretted hydrogen, 605 

Physostigma, 324, 328 

Physostigmin, 260, 324, 330 

Phytolacca, 436 

Pbytolaccatoxin, 436 

Pichi, 78 

Picis liquidse, oleum, 410 

emplastrum cantharidum, 92, 732 

Picrsena, 58 

Picric acid, 426 

Picroaconitine, 332 

Picropodophyllin, 105 

Picrotin, 436 

Picrotoxin, 436 

Pills, 40 

cathartic vegetable, 106 
compound cathartic, 106 

Pilocarpidine, 315 (note) 

Pilocarpine, 315, 330 

Pilocarpus, 314 

Pilulae, 40 

cathartic vegetable, 106 
composite, 106 



INDEX. 



751 



Pimenta, 68 
Pimpernel, scarlet, 711 
Pimpinella, 67 
Pineapple, 711 
Pink-root, 125 
Pinus, 86, 410 
Piper, 73 

angustifolium, 77 
cubeba, 76 
Piperazine, 553 
Piperidine, 72, 261, 264 
Piperine, 72 
Pipirinic acid, 72 
Pipsissewa, 78 
Pitch, Burgundy, 86, 732 

plaster, 87, 732 
Pituitary gland, 722 
Pituri, 268 
Piturin, 268, 281 
Pix, Burgundica, 86 
carbonis, 410 
liquida, 410 
Plasters, 30, 41, /31 

warming, 92 
Platinum, 703 
Plum stones, 239 
Plumbi suppositoria, co., 221 

cum opio, pilula, 221 
Plumbum, 674 
Plummer's pills, 637 
Podophyllotoxin, 105 
Podophyllum, 105, 107 
Poison ivy, 93 

oak, 93 
Poisons, 17 
Pokeberry, 436 
Pokeroot, 439 
Polygala, 351 
Polygalic acid, 351 
Polysolve, 356 
Pomegranate, 121 
Poplar, 418 
Poppy, red, 55 
Port wine, 147 
Potash, 549 

water, 584 
Potassa, 547 

sulphurata, 579 
Potassium action, 498 

acetate, 554 

arsenite, 620 

bicarbonate, 550 

bichromate, 704 

bitartrate, 540 

bromide, 508 

carbonate, 549 

chlorate, 526 

chloride, 498 

citrate, 535, 540 

ferroeyanide, 535 

hydrate, 54!) 

hypophosphite, 534 

iodate, 529 

iodide, 514 

lactate, 554 



Potassium malate, 535 

nitrate, 532 

nitrite, 468, 473 

oxalate, 557 

perchlorate, 520 

permanganate, 593 

persulphate, 593 

phosphate, 535 

propionate, 554 

relation to lime, 572 

salts, 498 

sozoiodolate, 523 

sulphate, 540 

sulphide, 579 

tartrate, 535, 540 

thiosulphate, 579 

valerianate, 554 
Potato, 281, 351 
Poultices, 41,86 
Powders, 40 

bleaching, 587 

dusting, 53 

Seidlitz, 541 
Precipitate, Avhite, 657 
Pregnancy, 26 
Preparations, alcoholic, 39 

aqueous, 38 

pharmacopoeia 1, 37 
Propionates, 554 
Propyl alcohol, 128, 146 

nitrite, 472 
Protargol, 696 
Protocurarine, 256 
Protocuridine, 256 
Protocurine, 256 
Protopine, 207, 219, 228 
Protoplasm poisons, 22 
Protoveratridine, 338 
Protoveratrine, 338 
Prune stones, 239 
Prunes, 59 

Primus amygdala, 48 
laurocerasus, 240 
Virginiana, 68. 240, 244 
Prussic acid, 48. 6S. 23!) 
Pseudaconitine, 332 
Pseudohyoscyamine, 280 
Pseudojervine. 338 
Pseudomorphino. 207 
Pseudostroph anthill, 441 
Psychotria, 34(5 
Pterooarpi lignum. 55 
PterocarpuSj 1 1 5 
Ptomatropine, 281 
Pulsatilla, 94 
Pnlveres, 40 
Pulvis, aromatic, 7 1 

effervescens <■<>.. 5 1 1 
Pumpkin Beed, 122 
Punica, 121 
Punicine, 121 
Purine bodies, 2 Hi 
Purgatives, 95, L04 
anthracene, 100 
effervescing, 5 1 1 



752 



INDEX. 



Purgatives, oily, 99 

saline, 535 

vegetable, ( .»."> 
Purging mils, 99 (note) 
Pustulants, 79 
Pyoctanine, 428 
Pyrethric acid, 72 
Pyrethrum, 72 
Pyridine, .'5."), 261, 284, 533 
Pyrocatechin, 300, 401 
Pyrodine, 374 
Pyrogallol, 390, 407 
Pyrophosphates, 539 
Pyro vanadates, 706 
Pyroxylin, 732 

QUAIRAMIDINE, 357 mote) 
Quairamine, 357 (note) 
Quassia, 58, 1 18 
Quassiin, 56, 57, 58 
Quebracho, 356 
Quercus, 115 
Quicksilver, 638 
Quillaja, 361, 355 
Quinamine, 357 (note) 
Quince, Bengal, 60 

seeds. 18 
Quinetum, 369 
Quinidine, 357, 366 
Quinic acid, 553 
Quinine, 357 

compared with antipyretics, 

hydrobromate, 508 

tasteless, 368 
Quinoidine, 369 
Quinoline, 35, 261, 264, 374 
Quinova red, 357 (note) 
Quinovin, 357 (note) 

EASPBERRY, 54 
Realgar, 607 
Rectified spirits, 146 
Rectum, application to, 31,34, 40 
Remijia, 357 
Remote action, 23 
Resin, 88, 732 
Resinous purges, 105 
Resins, 36 
Resopyrin, 374 
Resorcin, 390, 406 
Revulsion, theory of, 79 
Rhamnus purshiana, 104 
Rhatany, 114 
Rheum, 102 
Rhceadine, 207 
Rhoeados petala, 55 
Rhubarb, 100 
Rhus glabra, 115 

radicans, 94 

toxicodendron, 93 
Ricin, 724 

Ricinus, 99, 100, 724 
Roburite, 426 
Rochelle salt, 535 
Rosa, 67 
Rose, petals, 68 



388 



Rosi . < Ihrisl mas, 1 10 
Rosemary, oil ol 
Roses, ai tar, o\ to, oil of, 68 
Rosma rine, oleum, 68 
Rottlerin, 122 
Rubefacients, 79 
Rubidium, 199 
RBbijervine, 338 
Rubus, 1 1 •") 

idams, 5 1 
Rum, 72, 146 
Rumex, I 1 5 



O ABADILLA, 338 

U Sabadine, 338 
Sabina. 68, H7 
Saccharides, -*w 
Saccharin, 55 
Saccharum, 5 1 

lact i-. 54 

Saffron, 55 

Sage, •'••"). *'> s 

Salamander, alkaloids of, 36 

Salep, -18 

Saliein.418 

Salicylates, lis 

Salicylic acid. 391,413 

Saline cal liart ics, 535 

Saliphen, 375, 417 
Salipyrine, 374 
Salithymol, 391, 417 
Salocoll, 37."> 
Salol, 391,417 
Salophen, 375 
Salt action, 485 

common, 490 

of sorrel, 568 
Saltpetre, 532 
Salts, dissociation of, 488 

ethereal, 129 

purgative, 535 

smelling, 556 
Salumin, 702 
Salves, 30, 40 
Salvia, 68 

Sal volatile, spirit of, 556 
Samandarine, 437 
Sambucus, 67 
Sandalwood, 75 

oil of, 75 

red, 55 
Sanders, 55 
Sanguinaria, 228 . 
Sanguinarine, 228 
Santalol, 75 
Santalum album, 76 

rubrum, 55 
Santonica, 125 
Santonin, 122 
Santoninoxim, 124 
Sapo, 87, 221, 731 
Saponaria, 351 
Saponin, 350 
Sapotoxin, 350 
Sarsae radix, 355 



INDEX. 



753 



Sarsaparilla, 351, 355 

Sarsaponin, 357 

Sassafras, 47, 68 

Sassy bark, 440 

Saturnine colic, palsy, 677 

Saunders, 55 

Savine, 65, 68, 87 

Scammony, 98, 107 

Schsenocaulon, 338 

Scheele's green, 607 

Schleich's infiltration anaesthesia, 311 

mixtures, 180 
Schmiedeberg's classification, 42 
Schweinfurth's green, 607 
Scilla, 440 

Pil. ipecac, cum, 221 
Scillain, 441 
Scillotoxin, 457 
Sclerotinic acid, 482 
Scoparin, 266 
Scopolamine, 279, 293 
Scopoleine, 280, 295 
Scopolia, 279, 295, 351 

atropoides, 281, 295 
Scopoline, 279 
Scorpion, 725 
Scurvy grass, 73 
Secale, 476 
Secaline, 477 
Secalintoxin, 477 
Secretions, internal, 714 
Securite, 426 
Sedine, 72 
Sedum acre, 72 
Seidlitz powder, 541 
Selenium, 706 
Semecarpus, 94 
Senega, 351, 355 
Senegin, 351 
Senna, 100, 102, 103 
Sepia, 576 

Septentrionaline, 336 
Serpentaria, 59 
Serpentary, 57 
Sesame oil, 51 
Sesquiterpenes, 61, 75 
Sevum, 50 

Sex, influence of, on dose, 26 
Sherry wine, 147 
Sidonal, 553 
Silver, 628, 691 

colloid, 696 
Sinalbin, 89 
Sinapis, 89 
Sinigrin, 89 

Size, influence of, on dose, 25 
Skin, application of drugs to, 30, 33 

irritants, 78 
Slippery elm, 47 
Smilacin, 351 
Smilax, 351,355 
Snake poison, 725 

root, 59 
Soap, 87, 221, 731 

bark, 351, 355 

48 



Soaps, compound pill of, 221 
Soapwort, 351 
Socaloin, 101 
Socatrine aloes, 103 
Soda, 549 

chlorinated, 581 

water, 584 
Sod83 chloratae, liquor, 587 
Sodium, acetate, 555 

arsenate, 620 

benzoate, 424 

bicarbonate, 550 

bisulphite, 534 

borate, 583 

bromate, 529 

bromide, 508 

butyrate, 554 

cacodylate, 622 (note) 

caprylate, 554 

carbonate, 550 

chlorate, 526 

chloride, 490 

citrate, 535, 554 

citrotartrate, 541 

ethylate, 549 

ferrocyanide, 535 

fluoride, 525 

fluorosilicate, 526 

formate, 554 

hydrate, 549 

hypophosphite, 534 

hyposulphite, 534 

iodate, 529 

iodide, 514 

lactate, 554 

malate, 535 

malonate, 559 

metacresotinate, 422 

nitrate, 532 

nitrite, 468, 473 

cenanthylate, 554 

orthocresotinate, 422 

oxalate, 557 

palmitate, 554 

paracresotinate, 422 

perchlorate, 529 

persulphate, 593 

phosphate, 540 

propionate, 554 

pyrophosphate, 540 

salicylate, 391,413,418 

silicate, 732 

sozoiodolate, 523 

stearate, 554 

succinate. .V>!) 

sulphate, 535,540 

sulphide, 577 

sulphite, 534 

Bulphocarbolate, 422 

sulphovinate, ">i 1 

tartrate. 585, 540 

thiosulphate, 59 i 
valerianate, 554 

Soft soap. 731 

Solanacese. alkaloids, 281 



754 



INDEX. 



Solanein, 351 
Solanine, 350, 351 
Solanidine, 351 
Solanum, 35] 
Solutions, 480 
Solutol, 405 
Solved, 405 
Solvines, 35G 
Soporifics, 187 
Sorrel, salts of, 568 
Sowbread, 351 
Sozoiodolates, 523 
Sozolic acid, 422 
Spanish fly, 91 
Sparteine, 201,266 
Spartium, 200 
Spearmint, (J7 

oil of, 08 
Spermaceti, 51 
Spermine, 723 
Sphacelinic acid, 476 
Spliacelotoxin, 477 
Spider poison, 725 
Spigelia, 125 
Spirits, 71, 146 
Spiritus, 39 

frumenti, 146 

rectificatus, 146 

vini gallici, 146 

of volatile oils, 69 
Spleen, extract of, 723 
Spruce fir, Norway, 86 
Squills, 440 

Squirting cucumber, 107 
Stannous salts, 700 
Staphisagria, 332, 330 
Star anise, 08 

blazing, 351 
Starch, 45, 48, 51, 53 

glycerite, 51 
Stavesacre, 332 
Stearates, 554 
Stearoptenes, 61, 430 
Stupe, turpentine, 87 
Sterculia, 245 
Sternutatories, 31 
St. Ignatius' bean, 204 
Stibine, 037 
Stimulation, 20 

Stomach and intestine, absorption 
from, 32 

administration by, 30 
Stonecrop, biting, 72 
Storax, 424 
Stramonium, 281, 295 
Strontium, 570 

acetate, 555 

bromide, 508, 577 

iodide, 514 
Strophantus, 440, 456 
Structure, chemical and pharmacolog- 
ical action of, 24 
Strychnine, 196, 204, 219 

comparison with atropine and 
caffeine, 282 



Strychnine, comparison with digatilis, 

401 
with picrotoxin, 437 
Strychnos, 196,204,256 

Styptic collodion, 114, 732 

Stypticine, 232 

Sty rax, 424 

Subarachnoid cocainization, 312 

Subcutaneous injection, 33 

Sublimate, corrosive, 054 

Succi, 40 

Succinates, 558 

Suet, 50 

Sugar, 45, 54 

of lead, 07.") 
Sulphanilic acid, 516 
Sulphates, 535,539 
Sulphides, 577 
Sulphites, 533 

Sulphocarbolates, 391, 422, 690, 700 
Sulphonal, 129, 191 
Sulphovinate, 541 
Sulphur, 577 

flowers of, 580 

iodide, 518 

milk of, 580 

sublimated, 580 

washed, 580 
Sulphuretted hydrogen, 57!» 
Sulphuric acid, 504 

ether, 178 
Sulphuris, hepar, 579 
Sulphurous acid, 566 
Sumach, 115 

Currier's, 436 
Sumbul, 74 
Sundew, 711 
Suppository, 31 

glycerin, 52 
Suppositories, 40 

Suprarenal capsule, extract of, 440. 163 
Suprarennin, 403 (note) 
Swamp dogwood, 427 (note) 
Swertia chirata, 59 
Symphorol, 254 
Synergists, 28 
Syrupus, 39, 54 

aromaticus, 70 
Systemic action, 23 
Syzygium, 730 

TABELL.E, 40 
Tablet triturates, 40 
Taka-diastase, 712 
Talc, 53 
Tamarind, 55 
Tanacetum, 08 
Tanghinia, 441 
Tanghinin, 441 
Tannal, 702 
Tannalbin, 110 
Tannic acid, 111 
Tannigen, 115 
Tannocol, 116 
Tannoform, 115 



INDEX. 






Tannopin, 115 
Tansy, 68, 117 
Tar, 391, 410 
Tarantula, 725 
Taraxacum, 59 
Tartar, cream of, 540 

emetic, 633 
Tartaric acid, 563, 568 
Tartrates, 535, 539 
Tea, 245, 254 
Teel oil, 51 
Tellurates, 707 
Tellurium, 706 
Terebene, 87 
Terebinthina, 86 
Terpenes, 61, 86 
Terpin hydrate, 87 
Testicle, extract of, 723 
Tetrachloride of carbon, 180 
Tetraiodpyrrol, 523 
Tetronal, 129, 192, 194 
Thalline, 374 
Thallium, 706 
Thea, 245 

Thebaine, 196, 204, 207, 218 
Theine, 245 (note) 
Theobroma, 245 
Theobromine, 245 
Theon, 255 
Theophylline, 245 
Therapeutics, 17 
Therapin, 727 
Thermifugine, 374 
Thermodine, 375 
Thevetia, 440 
Thevetin, 441 
Thilanin, 580 
Thioform, 700 
Thiol, 392, 412 
Thiosinamine, 90 
Thiosulphates, 533 
Thornapple, 281 
Thus Americanum, 86 
Thyme, 68, 405 
Thymol, 67, 71,390, 405 
Thymosalol, 417 
Thymus extract, 722 
Thyreoglobulin, 715 
Thyreoiodin, 715 (note) 
Thyroid extract, 715 
Thyroidism, 719 
Tin, 628, 706 
Tinctures, 39 
Tobacco, 268, 276, 283 

Indian, 278 
Tolerance, 27, 725 
Tolu, balsam of, 424 
Toluifera, 424 
Toluol, 390 

Tolutana, tinctura, 424 
Toluylendiamine, 427 
Tonka bean, 524 
Toot poison, 436 
Toughened caustic, 694 
Toxalbumin, 724 



Toxicodendron 93 
Toxicology, 17 
Toxiresin, 430 
Tragacanth, 47 
Tribromphenol, 402 
Trichloracetic acid, 568 
Trichlorphenol, 391 
Tricresol, 405 
Triiodocresol, 523 
Trimethyl-ammonium, 315, 504 
Trimethylamir.e, 128, 727 
Trinitrate of glycerin. HJ8 
Trinitrini, Liquor, 474 
Trional, 129, 192, 194 
Trioxy benzol, 407 
Triticum, 47 
Tritopine, 207 
Trituratio, 40, 107 
Trituration, 40 
Troches, 40 
Troehisci, 31,40 
Tropacocaine, 303, 310 
Tropeines, 280, 294 
Tropic acid, 279 
Tropine, 121, 279 
Tully's powder, 221 
Tumenol, 392 
Tungsten, 706 
Turlington's balsam, 424 
Turpentine, 117 

oil of, 86, 590 
Turpeth mineral, 657 

ULMUS, 47 
Uncaria, 114 
Uncomocomo, 118 ( note) 
Unguenta, 30, 40 
Unguentum, 50 
Upas tree, 440 
Uranium, 706 
Urari, 256 

Urea as a diuretic, 493 
Urechites. 440 
Urethane, 129, 192, 194 
Urethra, applications to. 31 
Urethral suppositories. 40 
Urginea maritima,456 
Urosin, 553 
Urotropine, 553 
Ursion, 77 
Ustilago, 483 
Uterus, applications to, 31 
Uva ursi, 77 

VAGINA, applieations to, 31 
Vaginal suppositoi 
Valerian, 74 
Valerianate^, 554 
Vallet's mass, 670 
Valyl, 74 
Vanadium, 706 
Vanilla, 68 
Vaseline, 50 

Vegetable astringents, 111 
cathartic pill, lot; 



756 



INDEX. 



Vegetable purgatives, !)•> 
Veratrine, 338 
Veral rum, 338 
Verbascum, 48 
Vermicides, 117 
Vermifuges, 117 
Veronica, 107 
Vesicans, collodium, 732 
Vesicants, 70 
Vienna paste, 540, 574 
Vina, 30 
Vinegar, 517 

medicated, 40 
Vini Gallici, spiritus, 146 
Vinum album, 147 

aurantii, 147 

rubrum, 147 

xericum, 147 
Vioform, 523 
Violet, 344 

sight, 122 
Virginian cherry, 68, 240, 244 

prune, 68 
Vitellus, 40 
Volatile oils, 61, 302, 430 

WAHOO, 107, 457 
Warburg's tincture, 368 
Warming plaster. 02. 732 
Wasb, black, 657 
Wasb, yellow, 657 
Washes, 80, 657 
Water, 400 

aerated, 504 

potash, 584 

soda, 584 
Waterglass, 732 
Waterhemloek, 436 
Watering places, 405 
Waters, iror <-~ 2 



Waters, medicated, 3S 

Wax, 51, 731 

\\ eight, influence of, on do 

\\ hiskey, 72, l i<; 

Willow, 418 

Wine, l 17 

\\ inc>. medicated, 30 

Wintergreen, oil of, 68, B91, 41s 

Witchhazel, 1 15 

Woodtar, 391 

Woolfat,50 

Woorali,256 

Woorara, 256 

Wormseed, American, 126 

Levant, 125 
Wormwood, 65, (is 
Wristdrop, <J7S 

XAXTIIIX, 246, 254 
Xanthopsia, 122 

Xeroforin, Too 
Xylol. 390 

YELLOW jasmine, 265 
sight, L22 
Serbs Male, 245 
Yolk of eg<r. 19 

glycerite of, 51 
Young's formula, 25 
Youpon,246 
Yttrium, 400 (note) 

7EA, 78 

/j Zinc 62S. 688 

Zinc-haemol. 689 

Zinc phosphide, 605, 600 

sozoiodolate, 523 

surphocarbolate, 422, 600 
Zincum, 680 
Zingiber, 68, 73 



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